Drug administration guides in dysphagia

Aim: The aim of this evaluation was to evaluate the use of Individualised Medication Administration Guides (IMAGs) for patients with dysphagia on one stroke ward over a 6month period. Background: Patients with dysphagia (PWD) are more likely to suffer an administration error than patients without swallowing difficulties. To both standardise and improve medicines administration to patients with dysphagia I-MAGs were introduced on one stroke ward over a 6 month period. Methods: A software package supported with data on current national guidelines on the administration of medicines to PWD was designed by a specialised pharmacist in dysphagia to enable him to create individualised medication administration guides for patients with dysphagia which stated how each medicine should be optimally prepared and administered. On completion of the pilot service a questionnaire was given to all nurses, pharmacist and speech and language therapists who had experienced the I-MAGs. All the professionals received the same questionnaire but questions relevant only to their practice were added to the nurse’s questionnaire. Results: Of 26 Healthcare professionals (HCPs) approached, 19 returned completed questionnaires. Higher variability was found in the 13 responses from the nurse respondents than in the ones from the 3 pharmacist and the 3 SALTs. 8 (61%) of the nurses felt more confident in their practice when I-MAGs were in place. 10 (76%) of the nurses admitted that the guides could sometimes increase the time of the administration, but saw that it made practice safer. All the pharmacists considered the recommendations in the guides useful and all the respondents with the exception of one nurse (12:13) would like this service to continue. Conclusion: I-MAGs were well received on the ward and they support individualised care for patients with dysphagia. But the guides needed additional pharmacist input and greater nursing time. Research to determine the cost effectiveness of I-MAGs is needed.

A phase II study of mitomycin C and oral etoposide for advanced adenocarcinoma of the upper gastrointestinal tract

Background: Mitomycin C and etoposide have both demonstrated activity against gastric carcinoma. Etoposide is a topoisomerase II inhibitor with evidence for phase-specific and schedule-dependent activity. Patients and method. Twenty-eight consecutive patients with advanced upper gastrointestinal adenocarcinoma were treated with intravenous (i.v.) bolus mitomycin C 6 mg/m2 on day 1 every 21 days to a maximum of four courses. Oral etoposide capsules 50 mg b.i.d. (or 35 mg b.i.d. liquid) were administered days 1 to 10 extending to 14 days in subsequent courses if absolute neutrophil count >1.5 x 109/l on day 14 of first course, for up to six courses. Results: Twenty-six patients were assessed for response of whom 12 had measurable disease and 14 evaluable disease. Four patients had a documented response (one complete remission, three partial remissions) with an objective response rate of 15% (95% confidence interval (95% CI) 4%-35%). Eight patients had stable disease and 14 progressive disease. The median survival was six months. The schedule was well tolerated with no treatment-related deaths. Nine patients experienced leucopenia (seven grade II and two grade III). Nausea and vomiting (eight grade II, one grade III), fatigue (eight grade II, two grade III) and anaemia (seven grade II, two grade III) were the predominant toxicities. Conclusion: This out-patient schedule is well tolerated and shows modest activity in the treatment of advanced upper gastrointestinal adenocarcinoma. Further studies using protracted schedules of etoposide both orally and as infusional treatment should be developed.

Platinum-based chemotherapy in metastatic breast cancer : current status

Cisplatin and carboplatin are active in previously untreated patients with metastatic breast cancer (MBC) with mean response rates (RRs) of 50 and 32%, respectively. In pretreated patients the RR to cisplatin/carboplatin monotherapy declines markedly to <10%. Cisplatin and carboplatin have been combined with many other cytotoxics. In first-line setting high activity has been observed in combination with taxanes or vinorelbine (RRs consistently ∼60%). It appears that these newer combinations are superior to older regimens with etoposide (RRs 30 to 50%) or 5-fluorouracil (RRs 40 to 60%). Cisplatin-/carboplatin-based regimens with infusional 5-FU and epirubicin/paclitaxel/vinorelbine achieve high RRs of around 60 to 80%. However these regimens are difficult to administer in all patients because they require central venous access for continuous 5-FU infusion. In pretreated MBC the combinations of cisplatin-taxane/vinorelbine/gemcitabine or carboplatin-docetaxel/vinorelbine yield RRs of 40 to 50%, which are higher than those achieved with platinum-etoposide/5-FU. In locally advanced disease cisplatin-based regimens achieve very high RRs (>80%). This would suggest that in chemotherapy-naïve patients platinum-based therapy might have an important role to play. Additionally the synergy demonstrated between platinum compounds, taxanes and herceptin, in preclinical and clinical studies is of immense importance and the results of the two ongoing Breast Cancer International Research Group randomized phase III studies are eagerly awaited. These studies may help clarify the role of platinum compounds in the treatment of metastatic and possibly early breast cancer. © 2003 Elsevier Ltd. All rights reserved.

A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Purpose: This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 μg/ml for five days (5d) or 1 μg/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. Patients and methods: EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity. Results: The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 109/1 after 5d and 5.0 x 109/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP. Conclusions: Although the number of patients entered into this trial was small, the low activity seen at 1 μg/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration- controlled studies with prolonged EP infusions are required.

Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. © 2003 by American Society of Clinical Oncology.

Combination therapy with gefitinib and rofecoxib in patients with platinum-pretreated relapsed non-small-cell lung cancer

Purpose: In non-small-cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) play major roles in tumorigenesis. This phase I/II study evaluated combined therapy with the EGFR tyrosine kinase inhibitor (TKI) gefitinib and the COX-2 inhibitor rofecoxib in platinum-pretreated, relapsed, metastatic NSCLC (n = 45). Patients and Methods: Gefitinib 250 mg/d was combined with rofecoxib (dose escalated from 12.5 to 25 to 50 mg/d through three cohorts, each n = 6). Because the rofecoxib maximum-tolerated dose was not reached, the 50 mg/d cohort was expanded for efficacy evaluation (n = 33). Results: Among the 42 assessable patients, there was one complete response (CR) and two partial responses (PRs) and 12 patients with stable disease (SD); disease control rate was 35.7% (95% CI, 21.6% to 52.0%). Median time to tumor progression was 55 days (95% CI, 47 to 70 days), and median survival was 144 days (95% CI, 103 to 190 days). In a pilot study, matrix-assisted laser desorption/ionization (MALDI) proteomics analysis of baseline serum samples could distinguish patients with an objective response from those with SD or progressive disease (PD), and those with disease control (CR, PR, and SD) from those with PD. The regimen was generally well tolerated, with predictable toxicities including skin rash and diarrhea. Conclusion: Gefitinib combined with rofecoxib provided disease control equivalent to that expected with single-agent gefitinib and was generally well tolerated. Baseline serum proteomics may help identify those patients most likely to benefit from EGFR TKIs. © 2007 by American Society of Clinical Oncology.

Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer

Background: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. Patients and methods: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2 on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m, followed by 250 mg/m2 weekly thereafter). Results: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. Conclusion: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone. © 2007 European Society for Medical Oncology.

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

Lyprinol : is it a useful anti-inflammatory agent?

The New Zealand green lipped mussel preparation Lyprinol is available without a prescription from a supermarket, pharmacy or Web. The Food and Drug Administration have recently warned Lyprinol USA about their extravagant anti-inflammatory claims for Lyprinol appearing on the web. These claims are put to thorough review. Lyprinol does have anti-inflammatory mechanisms, and has anti-inflammatory effects in some animal models of inflammation. Lyprinol may have benefits in dogs with arthritis. There are design problems with the clinical trials of Lyprinol in humans as an anti-inflammatory agent in osteoarthritis and rheumatoid arthritis, making it difficult to give a definite answer to how effective Lyprinol is in these conditions, but any benefit is small. Lyprinol also has a small benefit in atopic allergy. As anti-inflammatory agents, there is little to choose between Lyprinol and fish oil. No adverse effects have been reported with Lyprinol. Thus, although it is difficult to conclude whether Lyprinol does much good, it can be concluded that Lyprinol probably does no major harm.

Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells

Patients with metastatic melanoma or multiple myeloma have a dismal prognosis because these aggressive malignancies resist conventional treatment. A promising new oncologic approach uses molecularly targeted therapeutics that overcomes apoptotic resistance and, at the same time, achieves tumor selectivity. The unexpected selectivity of proteasome inhibition for inducing apoptosis in cancer cells, but not in normal cells, prompted us to define the mechanism of action for this class of drugs, including Food and Drug Administration-approved bortezomib. In this report, five melanoma cell lines and a myeloma cell line are treated with three different proteasome inhibitors (MG-132, lactacystin, and bortezomib), and the mechanism underlying the apoptotic pathway is defined. Following exposure to proteasome inhibitors, effective killing of human melanoma and myeloma cells, but not of normal proliferating melanocytes, was shown to involve p53-independent induction of the BH3-only protein NOXA. Induction of NOXA at the protein level was preceded by enhanced transcription of NOXA mRNA. Engagement of mitochondrial-based apoptotic pathway involved release of cytochrome c, second mitochondria-derived activator of caspases, and apoptosis-inducing factor, accompanied by a proteolytic cascade with processing of caspases 9, 3, and 8 and poly(ADP)-ribose polymerase. Blocking NOXA induction using an antisense (but not control) oligonucleotide reduced the apoptotic response by 30% to 50%, indicating a NOXA-dependent component in the overall killing of melanoma cells. These results provide a novel mechanism for overcoming the apoptotic resistance of tumor cells, and validate agents triggering NOXA induction as potential selective cancer therapeutics for life-threatening malignancies such as melanoma and multiple myeloma.

Varenicline decreases alcohol consumption in heavy-drinking smokers

Rationale Emerging evidence suggests that the α4β2 form of the nicotinic acetylcholine receptor (nAChR) modulates the rewarding effects of alcohol. The nAChR α4β2 subunit partial agonist varenicline (Chantix™), which is approved by the Food and Drug Administration for smoking cessation, also decreases ethanol consumption in rodents (Steensland et al., Proc Natl Acad Sci U S A 104:12518–12523, 2007) and in human laboratory and open-label studies (Fucito et al., Psychopharmacology (Berl) 215:655–663, 2011; McKee et al., Biol Psychiatry 66:185–190 2009). Objectives We present a randomized, double-blind, 16-week study in heavy-drinking smokers (n = 64 randomized to treatment) who were seeking treatment for their smoking. The study was designed to determine the effects of varenicline on alcohol craving and consumption. Outcome measures included number of alcoholic drinks per week, cigarettes per week, amount of alcohol craving per week, cumulative cigarettes and alcoholic drinks consumed during the treatment period, number of abstinent days, and weekly percentage of positive ethyl glucuronide and cotinine screens. Results Varenicline significantly decreases alcohol consumption (χ 2 = 35.32, p < 0.0001) in smokers. Although varenicline has previously been associated with suicidality and depression, side effects were low in this study and declined over time in the varenicline treatment group. Conclusions Varenicline can produce a sustained decrease in alcohol consumption in individuals who also smoke. Further studies are warranted to assess varenicline efficacy in treatment-seeking alcohol abusers who do not smoke and to ascertain the relationship between varenicline effects on smoking and drinking.

FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer

Resistance to chemotherapy and metastases are the major causes of breast cancer-related mortality. Moreover, cancer stem cells (CSC) play critical roles in cancer progression and treatment resistance. Previously, it was found that CSC-like cells can be generated by aberrant activation of epithelial–mesenchymal transition (EMT), thereby making anti-EMT strategies a novel therapeutic option for treatment of aggressive breast cancers. Here, we report that the transcription factor FOXC2 induced in response to multiple EMT signaling pathways as well as elevated in stem cell-enriched factions is a critical determinant of mesenchymal and stem cell properties, in cells induced to undergo EMT- and CSC-enriched breast cancer cell lines. More specifically, attenuation of FOXC2 expression using lentiviral short hairpin RNA led to inhibition of the mesenchymal phenotype and associated invasive and stem cell properties, which included reduced mammosphere-forming ability and tumor initiation. Whereas, overexpression of FOXC2 was sufficient to induce CSC properties and spontaneous metastasis in transformed human mammary epithelial cells. Furthermore, a FOXC2-induced gene expression signature was enriched in the claudin-low/basal B breast tumor subtype that contains EMT and CSC features. Having identified PDGFR-β to be regulated by FOXC2, we show that the U.S. Food and Drug Administration-approved PDGFR inhibitor, sunitinib, targets FOXC2-expressing tumor cells leading to reduced CSC and metastatic properties. Thus, FOXC2 or its associated gene expression program may provide an effective target for anti-EMT-based therapies for the treatment of claudin-low/basal B breast tumors or other EMT-/CSC-enriched tumors.