Neurodegenerative diseases are still a challenge for effective treatments. The high cost of approved drugs, severity of side effects, injection site pain, and restrictions on drug delivery to the Central Nervous System (CNS) can overshadow the management of these diseases. Due to the chronic and progressive evolution of neurodegenerative disorders and since there is still no cure for them, new therapeutic strategies such as the combination of several drugs or the use of existing drugs with new therapeutic applications are valuable strategies. Tetracyclines are traditionally classified as antibiotics. However, in this class of drugs, doxycycline and minocycline exhibit also anti-inflammatory effects by inhibiting microglia/macrophages. Hence, they have been studied as potential agents for the treatment of neurodegenerative diseases. The results of in vitro and in vivo studies confirm the effective role of these two drugs as anti-inflammatory agents in experimentally induced models of neurodegenerative diseases. In clinical studies, satisfactory results have been obtained in Multiple sclerosis (MS) but not yet in other disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), or Amyotrophic lateral sclerosis (ALS). In recent years, researchers have developed and evaluated nanoparticulate drug delivery systems to improve the clinical efficacy of these two tetracyclines for their potential application in neurodegenerative diseases. This study reviews the neuroprotective roles of minocycline and doxycycline in four of the main neurodegenerative disorders: AD, PD, ALS and MS. Moreover, the potential applications of nanoparticulate delivery systems developed for both tetracyclines are also reviewed.

Objectives: To determine the pharmacokinetic parameters of gentamicin in a population of 200 premature newborns and to investigate the influence of several clinical and physiopathological covariates on the pharmacokinetics of the drug. To validate the pharmacokinetic analysis performed in another population of 50 premature newborns. Methods: A total of 200 premature newborns were evaluated at the neonatal intensive care unit of Severo Ochoa Hospital (Madrid, Spain). Four hundred and seventeen serum drug concentrations were included. Mean gestational age (GA) was 32.19 ± 2.97 weeks, mean postnatal age (PNA) was 5.49 ± 5.41 days and mean body weight (BW) was 1.68 ± 0.63 kg. Fifty additional newborns were studied for validation (mean GA 32.62 ± 3.07 weeks, mean PNA 5.17 ± 3.77 days and mean BW 1.80 ± 0.67 kg). Dosing, serum gentamicin concentrations and 15 covariates were collected. Data analysis was performed with NONMEM. One- and two-compartment open models were evaluated. Four parameters were analysed with the two-compartment open model: clearance (CL), central volume (Vc), peripheral volume (Vp) and intercompartmental clearance (Q). Results and conclusions: The two-compartment open model was found to significantly better describe gentamicin pharmacokinetics in the neonate. More than PNA or GA, creatinine clearance (CL_CR) plays an important role in the elimination of gentamicin in premature newborns. Creatinine clearance is also related to GA. The appropriate dosing regimens given in accordance with the characteristics of the patients are 5 mg/kg/48 h and 4 mg/kg/24 or 36 h for neonates <32 weeks and ≥32 weeks of GA, respectively.