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Summary Bryostatin 1, a novel antineoplastic agent and protein kinase C (PKC) activator, has been found to induce myalgia (muscle pain) 48 h after administration in clinical trials. This is the dose-limiting toxicity and has restricted the duration of therapy in phase I trials. To investigate the mechanisms and try to increase toleration of the drug, we studied calf muscle metabolism of 14 patients at rest and during exercise and subsequent recovery using 31P magnetic resonance spectroscopy (MRS) before and 4 h, 48 -72 h and 1-2 weeks following bryostatin therapy. In resting muscle there was a significant (P<0.001) increase in the phosphodiester/adenosine 5'-triphosphate (PDE/ATP) ratio 48 h post bryostatin and in patients with myalgia compared with pre-bryostatin control studies. Following exercise, patients with myalgia showed significantly slower phosphocreatine (PCr) and ADP recovery half-time (P <0.05) suggesting impaired mitochondrial (oxidative) energy production, possibly due to a direct effect on the mitochondria or secondary to reduced blood flow. The apparent proton efflux rate following exercise was significantly reduced 4 h after bryostatin (P <0.05), suggesting reduced blood flow. The rate of post-exercise reoxygenation was studied in four patients by near-infrared spectroscopy 4 h post bryostatin. In three of these the rate was reduced, consistent with reduced muscle blood flow. Bryostatin 1 appeared to cause a long-lasting impairment of oxidative metabolism and proton washout from muscle, consistent with a vasoconstrictive action. Thus these studies provide evidence for two mechanisms of the dose-limiting toxicity for bryostatin. Prospective studies on the use of vasodilators to improve the tolerance of the drug should be carried out.

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Context Hypothalamic obesity is a rare, treatment-resistant form of obesity. In preliminary studies, the hypothalamic hormone oxytocin (OXT) has shown promise as a potential weight loss therapy. Objective To determine whether 8 weeks of intranasal OXT (vs. 8 weeks of placebo) promotes weight loss in children, adolescents, and young adults with hypothalamic obesity. Design Randomized, double-blind, placebo-controlled, cross-over pilot trial (NCT02849743). Setting Outpatient academic medical center. Participants Aged 10y to 35y, hypothalamic obesity from hypothalamic/pituitary tumors. Intervention Intranasal OXT (Syntocinon, 40 USP units/mL, 4 IU/spray) vs. excipient-matched placebo, 16-24 IU three times daily at mealtimes. Main outcome measure(s) Weight loss attributable to OXT vs. placebo, safety (adverse events). Results Of 13 individuals randomized (54% female, 31% pre-pubertal, median age 15.3y, IQR 13.3-20.6), 10 completed the entire study. We observed a non-significant within-subject weight change of -0.6 kg (95% CI: -2.7, 1.5) attributable to OXT vs. placebo. A subset (2/18 screened, 5/13 randomized) had prolonged QTc interval on electrocardiography (ECG) prior to screening and/or in both treatment conditions. Overall, OXT was well-tolerated, and adverse events (epistaxis and nasal irritation, headache, nausea/vomiting, and changes in heart rate, blood pressure, and QTc interval) were similar between OXT and placebo. In exploratory analyses, benefits of OXT for anxiety and impulsivity were observed. Conclusions In this pilot study in hypothalamic obesity, we did not detect a significant impact of intranasal OXT on body weight. OXT was well-tolerated, so future larger studies could examine different dosing, combination therapies, as well as potential psychosocial benefits.