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Only a small fraction of drugs widely used in neonatal intensive care units (NICU) are specifically authorized for this population. Even if unlicensed or off-label use is necessary, it is associated with increased adverse drug reactions, which must be carefully weighed against expected benefits. In particular, renal damage is frequent among preterm babies, and is considered a predisposing factor for the development of chronic kidney disease in adulthood. Apart from specific conditions affecting premature neonates (e.g. respiratory distress syndrome, perinatal asphyxia), drugs play an important role in impairing renal function because of well-known nephrotoxicity and/or interaction with renal developmental factors. From a review of the available studies on drug use in NICU patients, we identified and described the most commonly administered drugs that are correlated to renal damage. Early detection of kidney injury is becoming an essential aspects for clinicians because of the limited number of biomarkers applicable in the neonatal population. Postnatal changes of biochemical processes that influence pharmacokinetic and pharmacodynamic aspects need to be further investigated in order to better understand the mechanisms of drug toxicity in this population. The most promising strategies for dose adjustment and therapeutic schemes are discussed. The purpose of this review was to describe current knowledge on drug use among premature babies and their implication in kidney injury development, as well as to highlight available strategies for early detection of renal damage.

The present experiments were performed to investigate the possible role of histamine and its receptors, H1 and H2, in the control of PRL and LH release in normal adult humans of both sexes. Histamine infusion (200 microgram, iv, in 15 min) induced PRL and LH release in men; in women, histamine inhibited LH release without affecting PRL release. Two H1 antagonists, dexchlorpheniramine (10 mg, iv) and promethazine (50 mg, im), reduced PRL release in both sexes, stimulated LH release in men, and inhibited LH release in women. Cimetidine, an H2 antagonist (400 mg, iv), elicited PRL release in both sexes, more consistently in females than in males, and was without effect on LH release in either sex. These data suggest that in humans, the effect of histamine on PRL release is linked to H1 and H2 receptors, which respectively stimulate and inhibit PRL release independently of sex. The effect of histamine on LH release appears to depend on sex and to be mediated only by H1 receptors. To rule out the possibility that the effects of histamine are merely due to a nonspecific stress reaction, we have evaluated PRL and LH release in otherwise normal men and women undergoing surgery for gallstones. Surgery was accompanied by PRL release in both sexes, more evident in women, and by LH release only in men. These results indicate that the effect of histamine on PRL and LH release in humans is linked to sex and H1 and H2 receptors and is not due to stress; further studies are required to clarify the possible mechanism and site of action of histamine in modifying PRL and LH release in humans.

Notwithstanding recognized limitations, these findings strengthen the importance of exploring multiple databases in safety assessment of RYR products, which should be monitored by clinicians for muscular and hepatic safety, and call for urgent review by policymakers to harmonize their regulatory status.

BackgroundDrug use in preterm neonates admitted to Neonatal Intensive Care Unit (NICU) has been investigated, so far, in terms of unauthorized or off-label use; very little is known on the use of combinations of different active substances, which is frequently required in this population (prophylaxis of infections, treatment of concomitant diseases). The aim of this study was to describe the most common patterns of drug use in an Italian NICU, focusing on those with nephrotoxic potential.MethodsMedical records of preterm neonates (<37 weeks of gestational age) weighing less than 1,500 g at birth and admitted to an Italian NICU were scrutinized in a 3-year retrospective investigation. Analysis included drug exposure, duration of therapies, co-administration of drugs with potential renal side effects; also daily protein supplement was calculated from parenteral nutrition.ResultsA cohort of 159 preterm neonates was selected; 68 were born weighing less than 1,000 g (extremely low birth weight infants, ELBW, Group A), 91 weighed between 1,000 and 1,500 g at birth (Group B). Compared to Group B, neonates of Group A were more likely to receive pharmacological treatments: the most used drugs were antibiotics (especially ampicillin and amikacin, p = .07 and p < .001, respectively), antifungals (especially fluconazole, p < .001), and diuretics (especially furosemide, p < .001). Analysis of co-administration of drugs with potential nephrotoxicity showed ampicillin and amikacin as the most reported combination (94.1% of Group A and 31.9% of Group B), the combination of furosemide with antibacterials (ampicillin or amikacin) was also frequently reported, with average period of combination shorter than 2 days.ConclusionsELBW infants were exposed to a higher number of drugs compared to other neonates and were more likely to receive associations of drugs with nephrotoxic potential (e.g. furosemide and amikacin), though only for short cycles. Further studies should evaluate the safety profile (especially potential renal side effects) related to most commonly used combinations.

To evaluate the possible involvement of endogenous opioid peptides in the responses of PRL, LH, and cortisol to surgical stress, we have studied the effect of naloxone on these hormones in otherwise normal subjects of both sexes undergoing cholecystectomy for gallstones. In 24 subjects (12 males and 12 females), premedication consisted of atropine sulfate (0.007 mg/kg BW); general anesthesia (30 min later) was induced by thiopental (7 mg/kg) and maintained constant by 1% ethrane in a 70%:30% nitrous oxide-oxygen mixture. In 6 males and 6 females, naloxone (0.4 mg) was injected iv before anesthesia induction. After skin incision, a clear PRL release was observed in all subjects; this was more evident in females than in males. PRL release was significantly lower in naloxone-pretreated subjects. LH release was observed only in males and was significantly higher in naloxone-pretreated subjects. Cortisol release occurred in both sexes in a similar way and was not significantly different in naloxone-pretreated subjects. Cortisol release occurred in both sexes in a similar way and was not significantly different in naloxone-pretreated subjects. These results indicate that endogenous opioid peptides are involved in stress-induced PRL and LH release in humans.

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Background/Aim: Acute kidney injury is an important cause of mortality in very-low-birth-weight (VLBW) preterm infants. As in the general population, the detection of renal damage cannot rely on the measurement of serum creatinine, since it has been demonstrated to be a weak predictor and a delayed indicator of kidney function deterioration. However, several candidate biomarkers have failed to prove sufficient specificity and sensitivity for a routine clinical use because of the poor awareness of their biological role. This study was aimed to investigate the impact of different maternal and neonatal conditions on several renal biomarkers in VLBW preterm infants during the first week of life. Patients and Methods: Preterm infants<32 weeks' gestation and <1500g were enrolled. We measured urinary biomarkers kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, epidermal growth factor (EGF) and osteopontin (OPN) on the 1 st , 3 rd , and 7 th day after birth. Results: Thirty-tree infants were included. The multivariate analysis showed a significant association between gestational age, the presence of patent ductus arteriosus, antenatal maternal hypertension and the levels of urinary biomarkers. Conclusion: There is a possible relation between early biomarkers of renal injury and antenatal, perinatal and post-natal characteristics in VLBW preterm infants during the first week of life. Preterm birth is burdened by high rates of perinatal morbidity and mortality worldwide (1). With an estimated incidence of 12-18%, acute kidney injury (AKI) is among the main causes of mortality in the preterm population, and represents an independent predictor of mortality even after adjustment for confounding variables, namely comorbidities, interventions and demographic characteristics (2, 3). Preterm birth is also associated with an increased risk of cardiovascular and chronic kidney disease in adulthood; this poses important challenges for the clinicians to detect as soon as possible developmental and functional abnormalities that could affect lifetime (4, 5). In humans and experimental animals, however, measurable changes in serum creatinine and glomerular filtration rates can be evident only after a remarkable reduction in kidney function (less than 50-80% of normal values), being thus insensitive to detect subclinical renal damage. Moreover, serum creatinine levels can be influenced by several factors, such as gender, age, hydration state, muscle mass, ongoing medications and endogenous metabolites (e.g., bilirubin) (3, 6). In the neonatal population, AKI definitions based on serum creatinine are susceptible to specific additional limitations: in the first days of life, serum creatinine may reflect the maternal kidney function (7, 8) and it is not able to distinguish pre-renal injuries, which are often reversible and transient, from intrinsic renal injuries (9). Moreover, serum creatinine does not provide specific information on the type of kidney insult (e.g., toxic, infectious, ischemic...