-
1.
Association Between Gait Speed With Mortality, Cardiovascular Disease and Cancer: A Systematic Review and Meta-analysis of Prospective Cohort Studies.
Veronese, N, Stubbs, B, Volpato, S, Zuliani, G, Maggi, S, Cesari, M, Lipnicki, DM, Smith, L, Schofield, P, Firth, J, et al
Journal of the American Medical Directors Association. 2018;(11):981-988.e7
Abstract
OBJECTIVES Slow gait speed may be associated with premature mortality, cardiovascular disease (CVD), and cancer, although a comprehensive meta-analysis is lacking. In this systematic review and meta-analysis, we explored potential associations between gait speed and mortality, incident CVD, and cancer. DESIGN A systematic search in major databases was undertaken from inception until March 15, 2018 for prospective cohort studies reporting data on gait speed and mortality, incident CVD, and cancer. SETTING AND PARTICIPANTS All available. MEASURES The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs), based on the model with the maximum number of covariates for each study between gait speed (categorized as decrease in 0.1 m/s) and mortality, incident CVD, and cancer, were meta-analyzed with a random effects model. RESULTS Among 7026 articles, 44 articles corresponding to 48 independent cohorts were eligible. The studies followed up on a total of 101,945 participants (mean age 72.2 years; 55% women) for a median of 5.4 years. After adjusting for a median of 9 potential confounders and the presence of publication bias, each reduction of 0.1 m/s in gait speed was associated with a 12% increased risk of earlier mortality (45 studies; HR = 1.12, 95% CI: 1.09-1.14; I2 = 90%) and 8% increased risk of CVD (13 studies; HR = 1.08, 95% CI: 1.03-1.13; I2 = 81%), but no relationship with cancer was observed (HR = 1.00, 95% CI: 0.97-1.04; I2 = 15%). CONCLUSION/IMPLICATIONS Slow gait speed may be a predictor of mortality and CVD in older adults. Because gait speed is a quick and inexpensive measure to obtain, our study suggests that it should be routinely used and may help identify people at risk of premature mortality and CVD.
-
2.
A systematic review - Biologically-based complementary medicine use by people living with cancer - is a more clearly defined role for the pharmacist required?
Le, TQ, Smith, L, Harnett, J
Research in social & administrative pharmacy : RSAP. 2017;(6):1037-1044
Abstract
BACKGROUND Biologically-based complementary medicines (BB-CMs) including herbal, vitamin, mineral and nutritional supplements are frequently taken by people living with cancer. Pharmacists play an important and clearly defined role in the provision of standard cancer treatment. Due to the non-prescription status and easy access to BB-CMs, the role of the pharmacist in communicating to people living with cancer about their use is less clearly defined. AIM: To explore the role of the pharmacist in communicating to people living with cancer about their use of BB-CMs. METHODS Eligible studies were identified in PubMed, Medline, EmBase, International Pharmaceutical Abstracts and Google Scholar. Articles published between 2003 and 2016 were included searching for "Complementary OR Herbal medicine OR vitamin OR nutritional supplement"; and "cancer OR oncology patient"; and "pharmacist role OR attitude OR belief OR communication". RESULTS BB-CM use is prevalent among people living with cancer for the management of side effects and are taken under the belief they are safe, natural and holistic. Fifty per cent of cancer patients do not disclose their BB-CM use to their physicians due to a perception that it will be discouraged and/or their physician will not be knowledgeable about BB-CMs. There are known drug-herb/nutrient interactions but interestingly pharmacists are the least consulted health care professional (HCP). CONCLUSION With adequate knowledge about BB-CMs, pharmacists are well positioned as medication specialists to fill the current communication gap between people living with cancer and HCPs. Further research that informs the development of specific BB-CM guidelines for pharmacists in the management of cancer are required.
-
3.
Cantuzumab mertansine in a three-times a week schedule: a phase I and pharmacokinetic study.
Rodon, J, Garrison, M, Hammond, LA, de Bono, J, Smith, L, Forero, L, Hao, D, Takimoto, C, Lambert, JM, Pandite, L, et al
Cancer chemotherapy and pharmacology. 2008;(5):911-9
Abstract
PURPOSE Cantuzumab mertansine (SB-408075; huC242-DM1) is a conjugate of the maytansinoid drug DM1 to the antibody huC242, which targets CanAg antigen. In previous studies, cantuzumab mertansine was considered safe and tolerable, but transaminitis precluded tolerance of higher doses. Based on those studies, it was suggested that treatment at intervals of the half-life of the intact immunoconjugate may allow a higher dose density. This provided the rationale for the three-times weekly treatment explored in this protocol. METHODS Patients with advanced solid tumors and documented CanAg expression were treated with escalating doses of cantuzumab mertansine IV administered three-times a week in a 3 out of 4 weeks schedule. Plasma samples were assayed to determine pharmacokinetic parameters. RESULTS Twenty patients (pts) with colon (11/20), rectal carcinomas (2/20), or other malignancies (7/20) were treated with doses ranging from 30 to 60 mg/m2 per day of cantuzumab mertansine IV three-times a week. The maximum tolerated dose (MTD) was 45 mg/m2, and the dose-limiting toxicity was grade 3 transaminitis. Hepatic, hematologic, and neurosensory effects occurred, but were rarely severe with repetitive treatment at doses of 45 mg/m2. CONCLUSIONS Treatment with cantuzumab mertansine at 45 mg/m2 per day three-times weekly x 3-every-4-week schedule proved that a dose-intense treatment with an immunoconjugate can be safely administered. The pharmacokinetic profile of the intact immunoconjugate indicates that the linker is cleaved with a half-life of about 2 days, resulting in faster clearance of the maytansinoid relative to the antibody. Therefore, with the development of second-generation immunoconjugates, there is a need for improvement of the immunoconjugate linker to take full advantage of the slow clearance of full-length antibody molecules.
-
4.
Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study.
Tolcher, AW, Ochoa, L, Hammond, LA, Patnaik, A, Edwards, T, Takimoto, C, Smith, L, de Bono, J, Schwartz, G, Mays, T, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003;(2):211-22
Abstract
PURPOSE To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) directed to CanAg, intravenously (i.v.) once every 3 weeks and to seek evidence of antitumor activity. PATIENTS AND METHODS Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered i.v. every 3 weeks. The pharmacokinetic parameters of cantuzumab mertansine, the presence of plasma-shed CanAg, and the development of both human antihuman and human anti-DM1 conjugate antibodies also were characterized. RESULTS Thirty-seven patients received 110 courses of cantuzumab mertansine at doses ranging from 22 to 295 mg/m2. Acute, transient, and reversible elevations of hepatic transaminases were the principal toxic effects. Nausea, vomiting, fatigue, and diarrhea were common but rarely severe at the highest dose levels. Dose, peak concentration, and area under the concentration-time curve correlated with the severity of transaminase elevation. The mean (+/- SD) clearance and terminal elimination half-life values for cantuzumab mertansine averaged 39.5 (+/-13.1) mL/h/m2 and 41.1 (+/-16.1) hours, respectively. Strong expression (3+) of CanAg was documented in 68% of patients. Two patients with chemotherapy-refractory colorectal carcinoma had minor regressions, and four patients had persistently stable disease for more than six courses. CONCLUSION The recommended dose for cantuzumab mertansine is 235 mg/m2 i.v. every 3 weeks. The absence of severe hematologic toxic effects, preliminary evidence of cantuzumab mertansine tumor localization, and encouraging biologic activity in chemotherapy-refractory patients warrant further broad clinical development of this immunoconjugate in CanAg-expressing tumors.
-
5.
Phase I and pharmacokinetic study of BMS-184476, a taxane with greater potency and solubility than paclitaxel.
Hidalgo, M, Aylesworth, C, Hammond, LA, Britten, CD, Weiss, G, Stephenson, J, Schwartz, G, Patnaik, A, Smith, L, Molpus, K, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2001;(9):2493-503
Abstract
PURPOSE To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474. RESULTS Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean +/- SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 +/- 89 mL/min/m2, 402 +/- 231 L/m2, and 40.8 +/- 21.8 hours, respectively. CONCLUSION The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.
-
6.
A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077.
Britten, CD, Rowinsky, EK, Baker, SD, Weiss, GR, Smith, L, Stephenson, J, Rothenberg, M, Smetzer, L, Cramer, J, Collins, W, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2000;(1):42-9
Abstract
This Phase I study was performed to evaluate the tolerability and pharmacokinetic behavior of MKT-077, a water soluble rhodacyanine dye analogue, which partitions into tumor cell mitochondria where it is thought to act as a metabolic poison, leading to G1 arrest and apoptosis. Thirteen patients with advanced solid malignancies were treated with MKT-077 administered as a 30-min i.v. infusion weekly for 4 weeks every 6 weeks at doses ranging from 42 to 126 mg/m2/week. The principal toxicity was renal magnesium wasting, which was dose-limiting (grade 3) in one patient at each of the 84- and 126-mg/m2 dose levels. The other three patients at the 126-mg/m2 dose level developed grade 2 hypomagnesemia, which was cumulative in nature, improved with i.v. magnesium supplementation, and was controlled in two patients by the administration of prophylactic magnesium before and after treatment with MKT-077. Given the requirement for extensive monitoring of serum magnesium levels, dose escalation >126 mg/m2 was not considered feasible. Thus, the recommended dose for disease-oriented studies with this schedule of MKT-077 is 126 mg/m2/week. Pharmacokinetic studies revealed a prolonged terminal half-life (37 +/- 17 h) and a large volume of distribution (685 +/- 430 liters/m2). Clearance averaged 39 +/- 13 liters/h/m2. Peak MKT-077 plasma concentrations (1.2 +/-0.31 to 6.3 +/- 5.3 microg/ml) exceeded the IC50 concentrations required for human CX-1 colon, MCF-breast, CRL-1420 pancreas, EJ bladder, and LOX melanoma tumor cell lines in vitro (0.15-0.5 microg/ml). These results indicate that at the recommended dose level of 126 mg/m2/week of MKT-077, the toxicity profile was consistent with the preferential accumulation of the agent within tumor cell mitochondria, and biologically relevant plasma concentrations were achieved.