Testosterone Use in Adolescent Males: Current Practice and Unmet Needs.

Testosterone replacement therapy (TRT) is routinely prescribed in adolescent males with constitutional delay of growth and puberty (CDGP) or hypogonadism. With many new testosterone (T) formulations entering the market targeted for adults, we review current evidence and TRT options for adolescents and identify areas of unmet needs. We searched PubMed for articles (in English) on testosterone therapy, androgens, adolescence, and puberty in humans. The results indicate that short-term use of  T enanthate (TE) or oral  T undecanoate is safe and effective in inducing puberty and increasing growth in males with CDGP. Reassuring evidence is emerging on the use of transdermal  T to induce and maintain puberty. The long-term safety and efficacy of TRT for puberty completion and maintenance have not been established. Current  TRT regimens are based on consensus and expert opinion, but evidence-based guidelines are lacking. Limited guidance exists on when and how  T should be administered and optimal strategies for monitoring therapy once it is initiated. Only  TE and  T pellets are US Food and Drug Administration approved for use in adolescent males in the United States. Despite the introduction of a wide variety of new  T formulations, they are designed for adults, and their metered doses are difficult to titrate in adolescents. In conclusion, TRT in adolescent males is hindered by lack of long-term safety and efficacy data and limited options approved for use in this population. Additional research is needed to identify the route, dose, duration, and optimal timing for TRT in adolescents requiring androgen therapy.

Platelet Function: Meloxicam Intravenous in Whole Blood Samples From Healthy Volunteers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective treatments for pain but may induce bleeding events due to platelet dysfunction associated with inhibition of cyclooxygenase (COX)-1 impairing thromboxane production. An intravenous nanocrystal formulation of meloxicam, a COX-2 preferential nonsteroidal anti-inflammatory drug, is under development for the treatment of moderate to severe pain. This single-center ex vivo study evaluated the effect of meloxicam intravenous and ketorolac on platelet function in whole blood samples from healthy volunteers. Each whole blood sample was aliquoted to allow analysis using a platelet function analyzer under negative control (untreated), positive control (2 therapeutic ketorolac concentrations), and meloxicam intravenous (1 therapeutic, 3 supratherapeutic concentrations) using both collagen with epinephrine and collagen with adenosine diphosphate reagent cartridges. The platelet function analyzer determines closure time by simulating platelet adhesion and aggregation following vascular injury. The final analysis set included data from 8 subjects. The collagen with adenosine diphosphate analysis (sensitive to thrombocytopathies) showed no significant differences in closure time for meloxicam- or ketorolac-treated samples and untreated control. The collagen with epinephrine analysis (sensitive to aspirin-induced platelet abnormalities) produced no significant difference in closure time between any meloxicam concentration and untreated control. Ketorolac was associated with significantly longer closure times vs untreated control at both the 2.5- and 5-µg/mL concentrations (P = .003 and .0257, respectively) and vs meloxicam at several concentrations. Similar results were observed when all analyzed samples were included. Meloxicam intravenous had no significant effect on closure times at therapeutic or supratherapeutic concentrations in this ex vivo study.

Safety and efficacy of volume-based feeding in critically ill, mechanically ventilated adults using the 'Protein & Energy Requirements Fed for Every Critically ill patient every Time' (PERFECT) protocol: a before-and-after study.

BACKGROUND: Underfeeding in critical illness is common and associated with poor outcomes. According to large prospective hospital studies, volume-based feeding (VBF) safely and effectively improves energy and protein delivery to critically ill patients compared to traditional rate-based feeding (RBF) and might improve patient outcomes. A before-and-after study was designed to evaluate the safety, efficacy and clinical outcomes associated with VBF compared to RBF in a single intensive care unit (ICU). METHODS: The sample included consecutively admitted critically ill adults, mechanically ventilated for at least 72 h and fed enterally for a minimum of 48 h. The first cohort (n = 46) was fed using RBF, the second (n = 46) using VBF, and observed for 7 days, or until extubation or death. Statistical comparison of percentage feed volume, energy and protein delivered, plus indices of feed intolerance, were the primary outcomes of interest. Secondary observations included ventilation period, mortality, and length of ICU stay (LOICUS). RESULTS: Groups were comparable in baseline clinical and demographic characteristics and nutrition practices. Volume delivered to the VBF group increased significantly by 11.2% (p ≤ 0.001), energy by 13.4% (p ≤ 0.001) and protein by 8.4% (p = 0.02), compared to the RBF group. In the VBF group, patients meeting > 90% of energy requirements increased significantly from 47.8 to 84.8% (p ≤ 0.001); those meeting > 90% of protein requirements changed from 56.5 to 73.9% (p = 0.134). VBF did not increase symptoms of feed intolerance. Adjusted binomial logistic regression found each additional 1% of prescribed feed delivered decreased the odds of vomiting by 0.942 (5.8%), 95% CI [0.900-0.985], p = 0.010. No differences in mortality or LOICUS were identified. Kaplan-Meier found a significantly increased extubation rate in patients receiving > 90% of protein requirements compared to those meeting < 80%, (p = 0.006). Adjusted Cox regression found the daily probability of being extubated tripled in patients receiving > 90% of their protein needs compared to the group receiving < 80%, hazard ratio 3.473, p = 0.021, 95% CI [1.205-10.014]. CONCLUSION: VBF safely and effectively increased the delivery of energy and protein to critically ill patients. Increased protein delivery may improve extubation rate which has positive patient-centred and financial implications, warranting larger confirmatory trials. This investigation adds weight to the ICU literature supporting VBF, and the growing evidence which advocates for enhanced protein delivery to improve patient outcomes.

Intravenous meloxicam for the treatment of moderate to severe acute pain: a pooled analysis of safety and opioid-reducing effects.

BACKGROUND AND OBJECTIVES: To describe the safety and tolerability of intravenous meloxicam compared with placebo across all phase II/III clinical trials. METHODS: Safety data and opioid use from subjects with moderate to severe postoperative pain who received ≥1 dose of intravenous meloxicam (5-60 mg) or placebo in 1 of 7 studies (4 phase II; 3 phase III) were pooled. Data from intravenous meloxicam 5 mg, 7.5 mg and 15 mg groups were combined (low-dose subset). RESULTS: A total of 1426 adults (86.6% white; mean age: 45.8 years) received ≥1 dose of meloxicam IV; 517 (77.6% white; mean age: 46.7 years) received placebo. The incidence of treatment-emergent adverse events (TEAEs) in intravenous meloxicam and placebo-treated subjects was 47% and 57%, respectively. The most commonly reported TEAEs across treatment groups (intravenous meloxicam 5-15 mg, 30 mg, 60 mg and placebo, respectively) were nausea (4.3%, 20.8%, 5.8% and 25.3%), headache (1.5%, 5.6%, 1.6% and 10.4%), vomiting (2.8%, 4.6%, 1.6% and 7.4%) and dizziness (0%, 3.5%, 1.1% and 4.8%). TEAE incidence was generally similar in subjects aged >65 years with impaired renal function and the general population. Similar rates of cardiovascular events were reported between treatment groups. One death was reported (placebo group; unrelated to study drug). There were 35 serious adverse events (SAEs); intravenous meloxicam 15 mg (n=5), intravenous meloxicam 30 mg (n=15) and placebo (n=15). The SAEs in meloxicam-treated subjects were determined to be unrelated to study medication. Six subjects withdrew due to TEAEs, including three treated with intravenous meloxicam (rash, localized edema and postprocedural pulmonary embolism). In trials where opioid use was monitored, meloxicam reduced postoperative rescue opioid use. CONCLUSIONS: Intravenous meloxicam was generally well tolerated in subjects with moderate to severe postoperative pain. TRIAL REGISTRATION NUMBERS: NCT01436032, NCT00945763, NCT01084161, NCT02540265, NCT02678286, NCT02675907 and NCT02720692.