Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study

Abstract

Twenty-one adult patients were randomised to receive ghrelin on days 1 and 8 and placebo on days 4 and 11 or vice versa, given intravenously over a 60-min period before lunch: 10 received 2 mg kg À1 (lower-dose) ghrelin; 11 received 8 mg kg À1 (upper-dose) ghrelin. Active and total ghrelin, growth hormone (GH), and insulin-like growth factor 1 levels were monitored at baseline (4 -5 days before day 1), during treatment days, and at end of study (day 17/18). Drug-related adverse events (assessed by NCI-CTC-toxicity criteria and cardiac examination) did not differ between ghrelin and placebo. No grade 3/4 toxicity or stimulation of tumour growth was observed. The peak increase of GH, a biological marker of ghrelin action, was 25 ng ml À1 with lower-dose and 42 ng ml À1 with upper-dose ghrelin. Morning fasting total ghrelin levels were higher (Po0.05) for upper-dose patients at end of study (3580 pg ml À1 ) than at baseline (990 pg ml À1 ). Insulin-like growth factor 1 levels did not change. At day 8, 81% of patients preferred ghrelin to placebo as against 63% at the end of study. Nutritional intake and eating-related symptoms, measured to explore preliminary efficacy, did not differ between ghrelin and placebo. Ghrelin is well tolerated and safe in patients with advanced cancer. For safety, tolerance, and patients' preference for treatment, no difference was observed between the lower-and upper-dose group.

Effect of acute and regular exercise on growth hormone secretagogue receptor-1a expression in human lymphocytes, T cell subpopulation and monocytes

“…Ghrelin expression by T cells is also reduced in ageing mice and ghrelin infusion in this model has been shown to reduce levels of IL-6, TNF-α and IL-1β (Dixit et al, 2009). Ghrelin infusion to improve lean body mass and appetite and decrease circulating inflammatory cytokines has had positive outcomes in patient populations with inflammation-related cachexia including cachetic cancer, cardiovascular disease, chronic obstructive pulmonary disease and chronic kidney disease (DeBoer, 2011;DeBoer et al, 2008;Nagaya et al, 2004Nagaya et al, , 2005Strasser et al, 2008). Our finding of increased GHS-R1a availability after exercise and a higher circulating proportion and concentration of GHS-R1a+ lymphocytes in active compared with sedentary individuals suggests that exercise prescription should be explored further as a tool to enhance the effectiveness of ghrelin therapy.…”

“…Our finding of increased GHS-R1a availability after exercise and a higher circulating proportion and concentration of GHS-R1a+ lymphocytes in active compared with sedentary individuals suggests that exercise prescription should be explored further as a tool to enhance the effectiveness of ghrelin therapy. Ghrelin is reported to be safe and well tolerated at doses of up to 10 μg.kg -1 (total ghrelin, Nagaya et al, 2001;Strasser et al, 2008) and 5 μg.kg -1 (acylated form; Akamizu et al, 2004) in both patient populations and healthy individuals with plasma concentrations of acylated ghrelin increasing by at least 30-fold after administration to around 3000-4000 pg.ml -1 (3-4 ng.ml -1 ) (Akamizu et al, 2004). Adverse effects of ghrelin administration are seemingly few; reports of shortlasting (minutes) and relatively mild abdominal discomfort and flushing are common and increases in plasma glucose and decreases in plasma insulin levels are also reported (Akamizu et al, 2004;Strasser et al, 2008).…”

“…Ghrelin is reported to be safe and well tolerated at doses of up to 10 μg.kg -1 (total ghrelin, Nagaya et al, 2001;Strasser et al, 2008) and 5 μg.kg -1 (acylated form; Akamizu et al, 2004) in both patient populations and healthy individuals with plasma concentrations of acylated ghrelin increasing by at least 30-fold after administration to around 3000-4000 pg.ml -1 (3-4 ng.ml -1 ) (Akamizu et al, 2004). Adverse effects of ghrelin administration are seemingly few; reports of shortlasting (minutes) and relatively mild abdominal discomfort and flushing are common and increases in plasma glucose and decreases in plasma insulin levels are also reported (Akamizu et al, 2004;Strasser et al, 2008). However, there are still unanswered questions concerning the effect of long-term ghrelin administration on growth hormone-mediated stimulation of tumour growth and there is the potential for ghrelin resistance with high plasma levels over a long period of time (Strasser et al, 2008).…”

“…Adverse effects of ghrelin administration are seemingly few; reports of shortlasting (minutes) and relatively mild abdominal discomfort and flushing are common and increases in plasma glucose and decreases in plasma insulin levels are also reported (Akamizu et al, 2004;Strasser et al, 2008). However, there are still unanswered questions concerning the effect of long-term ghrelin administration on growth hormone-mediated stimulation of tumour growth and there is the potential for ghrelin resistance with high plasma levels over a long period of time (Strasser et al, 2008). In this regard and considering the increased availability of GHS-R1a with exercise, future in vitro work should determine whether the concentration of acylated ghrelin required to elicit inhibitory effects on T cell and monocyte inflammatory cytokine release is lower after acute exercise or in active compared with sedentary individuals at rest.…”

“…However, while initial findings have been promising, the safety of long-term ghrelin treatment is still unknown (Strasser et al, 2008;DeBoer, 2011).…”