An estimated 70% of critically ill patients receive antibiotics, most frequently beta-lactams. The pharmacokinetic properties of these substances in this patient population are poorly predictable. Therapeutic drug monitoring (TDM) is helpful in making personalized decisions in this field, but its overall impact as a clinical decision-supporting tool is debated. We aimed to evaluate the clinical implications of adjusting beta-lactam dosages based on TDM in the critically ill population by performing a systematic review and meta-analysis of available investigations. Randomized controlled trials and observational studies were retrieved by searching three major databases. The intervention group received TDM-guided beta-lactam treatment, that is, at least one dose reconsideration based on the result of the measurement of drug concentrations, while TDM-unadjusted dosing was employed in the comparison group. The outcomes were evaluated using forest plots with random-effects modeling and subgroup analysis. Eight eligible studies were identified, including 1044 patients in total. TDM-guided beta-lactam treatment was associated with improved clinical cure from infection [odds ratio (OR): 2.22 (95% confidence interval (CI): 1.78–2.76)] and microbiological eradication [OR: 1.72 (CI: 1.05–2.80)], as well as a lower probability of treatment failure [OR: 0.47 (CI: 0.36–0.62)], but the heterogeneity of studies was remarkably high, especially in terms of mortality (70%). The risk of bias was moderate. While the TDM-guided administration of beta-lactams to critically ill patients has a favorable impact, standardized study designs and larger sample sizes are required for developing evidence-based protocols in this field.

Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CB₁Rs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females. We aimed to study the impact of ECS on vascular functions. Experiments were performed on CB₁R knockout (CB₁R KO) and wild-type (WT) female mice. Plasma estrogen metabolite levels were determined. Abdominal aortas were isolated for myography and histology. Vascular effects of phenylephrine (Phe), angiotensin II, acetylcholine (Ach) and estradiol (E2) were obtained and repeated with inhibitors of nitric oxide synthase (NOS, Nω-nitro-L-arginine) and of cyclooxygenase (COX, indomethacin). Histological stainings (hematoxylin-eosin, resorcin-fuchsin) and immunostainings for endothelial NOS (eNOS), COX-2, estrogen receptors (ER-α, ER-β) were performed. Conjugated E2 levels were higher in CB₁R KO compared to WT mice. Vasorelaxation responses to Ach and E2 were increased in CB₁R KO mice, attenuated by NOS-inhibition. COX-inhibition decreased Phe-contractions, while it increased Ach-relaxation in the WT group but not in the CB₁R KO. Effects of indomethacin on E2-relaxation in CB₁R KO became opposite to that observed in WT. Histology revealed lower intima/media thickness and COX-2 density, higher eNOS and lower ER-β density in CB₁R KO than in WT mice. CB₁R KO female mice are characterized by increased vasorelaxation associated with increased utilization of endothelial NO and a decreased impact of constrictor prostanoids. Our results indicate that the absence or inhibition of CB₁Rs may have beneficial vascular effects.

Purpose: Defective function of phenylalanine hydroxylase in phenylketonuria (PKU) results in the accumulation of phenylalanine (Phe) and the reduction of tyrosine (Tyr) in the blood, interfering in the normal development and function of organs and tissues in the body. Tyr is the precursor of catecholamines, secreted in response to stress by the adrenal medulla and paraganglia. The aim of this study was to evaluate plasma catecholamine and amino acid response to an escalating series of sympathetic stress tests in PKU patients.Methods: Twelve males with classical PKU (aged 18–41 years) and ten healthy male controls were included in this study. The subjects were exposed to three different sympathetic stress stimulations: cold pressor, isometric handgrip, and peak treadmill tests to exhaustion. Physiological, metabolic, and hormonal changes were determined.Results: Aerobic capacity (VO_2max) was significantly lower in the PKU group (p = 0.018); however, relative VO_2maxwas similar in the two groups during the spiroergometric test. No significant differences in norepinephrine or in epinephrine response were found between the two groups during the different stimulation tests. Blood Phe increased significantly in the PKU group compared with controls (p = 0.027) during the spiroergometric test, while Tyr levels remained stable in both groups.Conclusion: PKU itself might not influence stress-induced catecholamine changes. Only strenuous exercise increased blood Phe levels in PKU subjects.