The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial.

BACKGROUND: Cachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation. METHODS: A 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men (>60 years of age) and postmenopausal women. The primary endpoint was total lean body mass assessed by dual energy X-ray absorptiometry, and secondary endpoints included physical function, body weight, insulin resistance, and safety. RESULTS: GTx-024 treatment resulted in dose-dependent increases in total lean body mass that were statistically significant (P < 0.001, 3 mg vs. placebo) and clinically meaningful. There were also significant improvements in physical function (P = 0.013, 3 mg vs. placebo) and insulin resistance (P = 0.013, 3 mg vs. placebo). The incidence of adverse events was similar between treatment groups. CONCLUSION: GTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated. GTx-024 may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.

Controlled trial of the subjective patient benefits of accompanied walking to the operating theatre.

A trial was carried out to determine if walking unpremedicated patients to the operating theatre would prove acceptable to the patients. One hundred surgical patients from a short-stay-ward were randomised into experimental (walked to theatre by ward nurse) and control (taken to theatre on a hospital trolley) groups. Seventy-eight patients responded to a questionnaire; a large majority indicated they would like to be given the choice of mode of conveyance and perceived this as an improvement in patient care. The results showed that a more favourable impression of walking to the theatre was given by patients who had actually experienced it, and of those given the opportunity to walk, almost all reported that it made them feel more relaxed. The findings are discussed in relation to patient choice, efficiency gains and a reduction in manual handling.

Protein tyrosine (de-)phosphorylation in head and neck squamous cell carcinoma.

Protein phosphorylation plays an important role in signal transduction of both normal and neoplastic cells. Since increased protein tyrosine phosphorylation may be associated with malignant transformation, we studied the activities of protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTPase) in patients with various head and neck tumors. Furthermore, we determined the patterns of tyrosine phosphorylated protein (P-tyr) in tissues by western blotting. Enzyme activities were studied in tumor and histologically normal, non-tumorous tissues of 54 patients and in 11 controls. P-tyr patterns were determined in 3 patients and 2 controls. PTK and PTPase activities were greater in tumor tissues than in normal tissue of the cancer patients as well as controls. P-tyr levels in tumors were also higher than in normal tissues. Additionally, PTK activity in normal tissue of tumor patients was significantly higher than in normal tissue of the control group. The same trend was observed for the PTPase activity and P-tyr levels.

Protein tyrosine kinase activity in laryngeal squamous cell carcinoma.

Oncogenes play an important role in the process of malignant transformation. Since many of the protein tyrosine kinases (PTK) are products of oncogenes, the aim of this study was to demonstrate whether an increased PTK activity could be found in head and neck tumors. By using a non-radioactive dot-blot assay, PTK activity was measured in tumor and normal tissues of 38 patients with laryngeal cancer. The control group consisted of 19 healthy persons. PTK activity in tumor cells was significantly higher (P < 0.001) than in normal cells of the tumor patients and normal controls. Additionally, the PTK activity in the normal mucosa of the tumor patients was significantly higher than in the normal mucosa of the control group.

Diagnosis of pyruvate kinase deficiency in a transfusion-dependent patient with severe hemolytic anemia.

In a 2-yr old girl a hemolytic anemia was present since birth requiring multiple blood transfusions. Pyruvate kinase deficiency was suspected on the basis of a marginal enzyme activity, but could not be established due to the presence of massive numbers of donor cells in her peripheral blood. However, by density fractionation we succeeded in the isolation of a small fraction of the patient's own cells, in which a severe pyruvate kinase deficiency could be detected. In contrast hexokinase and glucose-6-phosphate dehydrogenase activities were extremely high, which is indicative that a very immature cell population is present in this fraction. In immunofluorescence studies a clear crossreaction was apparent with anti M2-type pyruvate kinase antibodies, whereas only a faint reaction with anti L-type could be detected. Despite the presence of a slight amount of L-type immunoreactive material, the residual activity in the patient's cell fraction could only be attributed to M2-type pyruvate kinase as was shown by cellulose acetate electrophoresis.

Lysosomal enzymes in normal and leukemic B lymphocytes.

Eleven lysosomal enzyme activities were tested in lymphocytes from normal individuals and patients with chronic lymphocytic leukemia. The activities of all enzymes, except acid phosphatase, were significantly lower in the leukemic lymphocytes (p less than 0.001). In addition the activities were tested in purified T- and non-T lymphocytes and in monocytes. For most enzymes the activities are similar in the three cell types, except for alpha-D-galactosidase, arylsulphatase B and alpha-D-glucosidase, which are lower in T lymphocytes, and N-acetyl-beta-D-glucosaminidase which is lower in non-T cells. In T and B lymphoblastic cell lines the activities are within the range for leukemic lymphocytes. No differences were found between the T and the B cell lines.