Laura Cuzzolin

Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety

This review aims to give an updated overview of the worldwide situation of off-label and unlicensed drug use in the paediatric field, also taking into account the safety of this kind of treatment. A Medline and Embase search was performed between 1990 and 2006 and a total of 52 studies were identified and included in the systematic review. From the authors’ analysis of the literature, the extent of paediatric unlicensed/off label use is higher in neonatal and paediatric intensive care units and oncology wards, compared with primary care. Moreover, among the nine studies reporting the contribution of an off-label/unlicensed drug use to the occurrence of adverse events, the percentage of unlicensed and/or off-label prescriptions involved in an adverse drug reaction ranged between 23 and 60%. To ensure that children are not exposed to unnecessary risks, controlled clinical trials are required. In addition, future research should be directed towards the identification of individual drugs that cause serious adverse drug reactions and lack product information.

Unlicensed and off‐label uses of drugs in paediatrics: a review of the literature

The off‐label and unlicensed use of drugs to treat children is a common practice that occurs either in hospital or in the community. This derives from the fact that research for establishing drug efficacy and safety in children has not been carried out due to ethical problems, logistical difficulties, financial and legal concerns. In this work we report the studies available in literature documenting the extent of drug use in the paediatric field outside the recommendations of the license. From our analysis, a widespread attitude to prescribe medicines to children outside their product license either in the hospitals or in the community is confirmed. This suggests an immediate action for a more rationale use of drugs in paediatrics, to avoid exposing children and infants to unnecessary risks, but also to avoid depriving them of potentially effective and sometimes life‐saving therapies.

NSAID-Induced Nephrotoxicity from the Fetus to the Child

In this review we report data available from the literature on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the development of nephrotoxicity in the fetus, neonates and children. Up to the present day, several cases of severe and sometimes irreversible renal insufficiency have been described in neonates exposed to indomethacin prenatally or in the first days of life for treatment of patent ductus arteriosus (PDA). Until now, very few studies have been carried out on alternative treatments for PDA in preterm infants; ibuprofen has been shown to be as effective as indomethacin in closing the ductus in this patient group without affecting renal function. In children, NSAID-induced renal failure is a rare event and is usually reversible after discontinuation of the drug. However, caution should be taken when NSAIDs are administered to individuals with preexisting renal problems or with other potentially nephrotoxic drugs. In these situations, new approaches such as cyclo-oxygenase-2 selective inhibitors or prostanoid receptor selective antagonists could lead to alternative therapies for use in paediatrics.

Safety implications regarding use of phytomedicines

ObjectiveSince the approach of the general population to phytomedicine is that the therapy therapy is natural and therefore safe, the aim of this study was to investigate the relationship between the use of herbal compounds, alone or in combination with traditional drugs, and the appearance of side-effects among a sample of Italian women.MethodsOur research was conducted over a 5–month period in the outpatient ambulatories of an urban university general hospital. The sample population consisted of women who were interviewed about phytotherapy use on the basis of a pre-structured questionnaire.ResultsAmong 1,063 women contacted, 1,044 completed the interview and 491 (47%) reported taking at least one herbal compound in the last year; 272 women (55.4%) consumed only phytomedicines, while 219 (44.6%) also took traditional drugs. Seventy-three different herbal products were used, 32 were consumed in association with traditional drugs. Forty-seven of 491 (9.6%) women reported side-effects, 22 after taking only phytomedicines (8.1%), 25 in combination with traditional drugs (11.4%). The observed adverse manifestations included the following: gastrointestinal after dandelion, propolis or fennel; cardiovascular after liquorice, ginseng, and green tea; dermatological after propolis, thyme, arnica, and passionflower; and neurological after guarana and liquorice. Drugs taken in association and potentially involved in adverse reactions were NSAIDs, antibiotics, benzodiazepines, antihypertensives and oral contraceptives. In some cases (n=5), side-effects were so serious to justify an admission to the hospital. In 29/47 of cases (61.7%), the adverse reaction was not communicated to the doctor.ConclusionsOur data confirm that herbal products are largely taken on a self-treatment basis, and users have the convinction that these therapies are natural and therefore safe.

Anti-inflammatory potency and gastrointestinal toxicity of a new compound, nitronaproxen

Naproxen and its derivative nitronaproxen at the doses of 5 and 10 mg kg-1 were compared for their acute anti-inflammatory efficacy in a carrageenan oedema model and gastrointestinal toxicity in rats. Moreover, the effects of the two drugs were evaluated in the adjuvant arthritis, after chronic doses of 4 and 8 mg kg-1 administered orally for 18 days. The oedema reduction was maintained much longer (until 5 h) with nitronaproxen; the inhibition of arthritis was 50% or more with both doses of the examined drugs. From the histological examination of the stomachs, an extensive mucosal vasocongestion and haemorrhagic lesions have been observed in some rats treated with naproxen. The percentages of animals with ulcers were 50, 100 and 10 with naproxen 6 and 18 mg kg-1 and nitronaproxen 54 mg kg-1 respectively. A better gastrointestinal tolerability has been observed in arthritic and oedemic rats treated with nitronaproxen compared to naproxen: this could be due to the presence of nitric oxide that acts in maintaining the tissue perfusion and integrity.

Use of herbal products among 392 Italian pregnant women: focus on pregnancy outcome.

The present study aimed to explore the use of herbal products among a sample of Italian pregnant women and the possible influence of herbal consumption on pregnancy outcome.

Inhibition by sodium nitroprusside of the expression of inducible nitric oxide synthase in rat neutrophils

A well‐known nitric oxide (NO)‐releasing compound, sodium nitroprusside (SNP), decreases in a dose‐dependent manner NO synthase (NOS) activity induced in rat neutrophils by treatment with lipopolysaccharide (LPS). This inhibitory action of SNP seems not to be due to its direct effect on the enzyme activity. The strong nitrosonium ion (NO+) character of SNP could be responsible for its inhibition of NOS induction in neutrophils.

Antibiotics and Antifungals in Neonatal Intensive Care Units: A Review

Abstract The incidence of infections is higher in the neonatal period than at any time of life. The basic treatment of infants with infection has not changed substantially over the last years. Antibiotics (with or without supportive care) are one of the most valuable resources in managing sick newborn babies. Early-onset (ascending or transplacental) or late-onset (hospital acquired) infections present different chronology, epidemiology, physiology and outcome. Some classes of antibiotics are frequently used in the neonatal period: penicillins, cephalosporins, aminoglycosides, glycopeptides, monobactams, carbapenems. Other classes of antibiotics (chloramphenicol, cotrimoxazole, macrolides, clindamycin, rifampicin and metronidazole) are rarely used. Due to emergence of resistant bacterial strains in Neonatal Intensive Care Units (NICU), other classes of antibiotics such as quinolones and linezolid will probably increase their therapeutic role in the future. Although new formulations have been developed for treatment of fungal infections in infants, amphotericin B remains first-line treatment for systemic Candida infection. Prophylactic antibiotic therapy is almost always undesirable. Challenges from pathogens and antibiotic resistance in the NICU may warrant modification of traditional antibiotic regimens. Knowledge of local flora and practical application of different antibiotic characteristics are key to an effective and safe utilization of antibiotics and antifungals in critical newborns admitted to the NICU, and especially in very low birth weight infants.

Efficacy and renal tolerability of ibuprofen vs. indomethacin in preterm infants with patent ductus arteriosus

Indomethacin is commonly used for the treatment of patent ductus arteriosus (PDA) but has renal failure as a main side‐effect. Ibuprofen seems to be efficient in closing the ductus with less side‐effects, but few studies are available in literature as regards its use in preterm infants. This study is a retrospective analysis of clinical data in order to compare the efficacy and the renal tolerability of ibuprofen and indomethacin administered to preterm infants with gestational age (GA) ≤30 weeks for the treatment of PDA. From our data, ibuprofen results pharmacologically as efficient as indomethacin and could be an alternative in prematures. About renal tolerability, our data confirm that non‐steroidal anti‐inflammatory drugs treatment could affect at least transiently renal function. Moreover, indomethacin could be more nephrotoxic compared with ibuprofen, as creatinine concentrations normalize more slowly in this group, although the mean difference between the two drugs was not significant as our population sample was small. Further studies are needed to assess whether ibuprofen is really less nephrotoxic than indomethacin, in particular by examining carefully the correlation between GA and ibuprofen administration.

Effect of a new non‐steroidal anti‐inflammatory drug, nitroflurbiprofen, on the expression of inducible nitric oxide synthase in rat neutrophils

The effects of a non‐steroidal anti‐inflammatory drug, flurbiprofen, and its nitro‐derivative, nitroflurbiprofen, on inducible nitric oxide synthase in rat neutrophils were examined. Nitroflurbiprofen was shown to inhibit nitric oxide synthase induction caused by lipopolysaccharide administration, while flurbiprofen had no effect on nitric oxide synthase induction. This inhibitory action may be ascribed to nitric oxide released from nitroflurbiprofen.