Current Drug Metabolism (v.14, #2)
Editorial (Hot Topic: Recent Advances in Neonatal Pharmacology) by Roberto Antonucci (159-159).
Antenatal Glucocorticoids Supplementation and Central Nervous System Development by Diego Gazzolo, Laura D. Serpero, Alessandro Frigiola, Raul Abella, Alessandro Giamberti, Giovanni Li Volti, Fabrizio Michetti (160-166).
Maternal antenatal therapy with glucocorticoids (GC) is routinely used to prevent lung immaturity. The potential harmful effects on other organs, including in particular the central nervous system (CNS), are still controversial. In the present review we aimed to investigate: i) the beneficial and detrimental effects of antenatal GC treatment in both human and animal models; ii) the potential usefulness of biochemical markers such as calcium binding proteins (S100B, synaptophysin) and cytoskeletal protein of neurons and dendrites (MAP2) in the perinatal period, and iii) whether the assessment of brain markers in different biological fluids could constitute a promising tool for the monitoring of CNS function and/or developmental in fetuses and newborns whose mothers assumed GC antenatally.
Drug Metabolizing Enzymes in the Perinatal and Neonatal Period: Differences in the Expression and Activity by Laura Cuzzolin (167-173).
Physiological changes occurring perinatally and in the first month of life can affect the answer to a pharmacological treatment and the individual response to a drug in terms of efficacy and toxicity is highly variable in the neonatal population. Among potential causes for such variability, differences in drug metabolism may have a great impact. This article aims to review qualitative and quantitative differences in drug metabolizing enzymes in neonates, since both phase I and phase II metabolic pathways are immature at birth and subject to maturational changes in the first period of extrauterine life. Moreover, clinical implications will be discussed.
The Neonatal Kidney: Implications for Drug Metabolism and Elimination by I. Ligi, F. Boubred, I. Grandvuillemin, U. Simeoni (174-177).
The kidney is a major organ for drug elimination. The function of the neonatal kidney is markedly immature with a reduction of renal blood flow, of glomerular filtration and of active tubular secretion, even in healthy, term infants. Maturation of renal function in particular of glomerular filtration rate is gestational age and postnatal age-dependant. Moreover, many neonatal pathological conditions such as preterm birth, sepsis or perinatal asphyxia can also affect renal function. These developmental changes have a major impact on drug metabolism and elimination. Alterations in renal clearance can influence significantly both drugs efficacy and toxicity. Moreover, nephrogenesis is a still ongoing process in a number of premature infants before 36 wks postconceptional age. Drugs and toxic factors that may alter the constitution of the congenital nephron number endowment during this period may have long term consequences on arterial pressure and renal function at adulthood.
Paracetamol (Acetaminophen) Efficacy and Safety in the Newborn by Laura Cuzzolin, Roberto Antonucci, Vassilios Fanos (178-185).
Neonates can perceive pain, therefore an adequate analgesic therapy is a major issue not only from an ethical perspective but also to improve short- and long-term outcome. Fever during the neonatal period requires hospitalization and needs a treatment with an antipyretic agent because of the high risk of severe complications. Paracetamol (acetaminophen), the most commonly prescribed drug in paediatric patients for its analgesic and antipyretic effects, is the only agent recommended for use as an antipyretic in the newborn and has been recently proposed as a supplement therapy to opioids for postoperative analgesia. This article aims to give an updated overview on the use of paracetamol in newborns by presenting its pharmacological profile (mechanism of action, pharmacokinetics), recommendations for dosing regimens (oral or rectal administration: 25-30 mg/kg/day in preterm neonates of 30 weeks' gestation, 45 mg/kg/day in preterm neonates of 34 weeks' gestation, 60 mg/kg/day in term neonates; i.v. administration: indicatively 20-40 mg/kg/day depending on gestational age, with some differences among various guidelines) and clinical uses (more commonly as analgesic/antipyretic by oral or rectal route, but also i.v. in anaesthesia for postoperative analgesia and painful procedures in Neonatal Intensive Care Units). Moreover, drug tolerability is discussed in the light of its potential hepatotoxicity and the unique characteristics of the newborn patient. By analyzing the available literature and the dosing guidelines, a mismatch exists between the current clinical use of paracetamol and the recommendations, suggesting a cautious approach particularly in extremely preterm neonates.
Vasopressin and Terlipressin in Neonates and Children with Refractory Septic Shock by Paolo Biban, Marcella Gaffuri (186-192).
Vasopressin and its analogue terlipressin are potent vasopressors which have been recently proposed in the treatment of catecholamine-resistant septic shock. We review the physiology, metabolism and pharmacology of vasopressin and terlipressin, as well as the available data on their efficacy and safety in neonates and children with septic shock. In adults, vasopressin deficiency can contribute to refractory shock states associated with sepsis. Differently, in children with septic shock vasopressin levels may be normal or even augmented. Nevertheless, low doses of vasopressin and terlipressin seem to have the potential to restore vasomotor tone in conditions refractory to catecholamines, improving organ perfusion with preservation of renal blood flow, while decreasing catecholamine requirements. Vasopressin and terlipressin produce vasoconstriction via stimulation of V1-receptors. In particular, terlipressin has a higher selectivity for V1-receptors and a longer half-life when compared to vasopressin, allowing for intermittent bolus doses. However, the pharmacology of vasopressin/terlipressin in newborns and children has not been sufficiently investigated and data on potential short and long-term adverse effects are still lacking. Further clinical, pharmacokinetic and pharmacodynamic studies are needed to better define the role of vasopressin and terlipressin in septic shock, as well as to prove their effectiveness and safety in infants and children.
Triazole Use in the Nursery: Fluconazole, Voriconazole, Posaconazole, and Ravuconazole by Kevin Watt, Paolo Manzoni, Michael Cohen-Wolkowiez, Stefano Rizzollo, Elena Boano, Evelyne Jacqz-Aigrain, Daniel K. Benjamin (193-202).
Invasive fungal infections in infants admitted to the neonatal intensive care unit are common and often fatal. The mainstay of therapy against invasive fungal infections is antifungal agents. Over the last two decades, the development and approval of these drugs evolved tremendously, and the azole class emerged as important agents in the treatment and prevention of invasive fungal infections. Among the azoles, fluconazole has been used extensively due to its favorable pharmacokinetics, excellent activity against Candida spp, and safety profile. This drug has been well studied in children, but data for its use in infants are largely limited to Candida prophylaxis studies. Voriconazole, a second generation triazole, has excellent activity against Candida and Aspergillus spp. However, data on its use in neonates are extremely limited. Posaconazole and ravuconazole are the newest agents of the triazole family. The antimicrobial spectrum of posaconazole is similar to voriconazole, but with additional activity against zygomycetes. Experience with posaconazole in children is very limited, and there are no reports of its use in infants. Ravuconazole is not approved for use by the FDA, but studies in animals and humans show that it is often fungicidal and has favorable pharmacokinetics. In conclusion, the management of invasive fungal infections has progressed greatly over the last two decades with the azole antifungals playing a significant role. Related to this class, future research is needed in order to better assess dosing, safety, schedules and areas of use of these agents in infants admitted to the neonatal intensive care unit.
Echinocandins for the Nursery: An Update by Paolo Manzoni, Daniel K. Benjamin, Caterina Franco, Stefano Rizzollo, Mauro Stronati, Kevin Watt, Michael Cohen-Wolkowiez, Evelyne Jacqz-Aigrain (203-207).
As the incidence rates of neonatal invasive fungal infection (IFI) have been increasing over the last years, research efforts have been addressed towards identifying both effective preventative strategies, and efficacious and well-tolerated antifungal drugs. Historically, the first options in treatment of neonatal IFI have been –and currently are- fluconazole and amphotericin B. However, these two drugs carry limitations both in efficacy and in putative toxicity. Recently, new therapeutic alternatives have drawn the neonatologists’ attention. Echinocandins are a new class of antifungal drugs with characteristics that might better meet the needs of this particular population of patients. Caspofungin, Micafungin and Anidulafungin have inherent good activities both against biofilms, and against natively fluconazole-resistent strains of Candida spp, thus overcoming two of the major weaknesses of the commonly used antifungal drugs in nurseries. Caspofungin and Micafungin have been recently studied in neonatal populations. The kinetics and appropriate dosing of this agent in premature and term infants have been described, but ongoing further studies are needed to better address this area. Extrapolation of data from randomized trials conducted in pediatric and adult patients showed through a subgroup analysis that both Caspofungin and Micafungin are effective and well tolerated also in neonates. Further studies properly designed for neonatal populations will better address long-term safety and echological issues related to Echinocandin use in neonates.
Pharmacokinetics, Pharmacodynamics and Clinical Use of Valganciclovir in Newborns with Symptomatic Congenital Cytomegalovirus Infection by Mauro Stronati, Giuseppina Lombardi, Francesca Garofoli, Paola Villani, Mario Regazzi (208-215).
Congenital cytomegalovirus infection is the most common cause of nonhereditary sensorineural hearing loss and an important cause of psychomotor retardation. Newborns suffering from symptomatic congenital cytomegalovirus infection have been typically treated with i.v. ganciclovir (GCV). Nowadays valganciclovir (V-GCV), a mono-valyl ester pro-drug of GCV, is available as an oral syrup. The existing literature demonstrated that V-GCV is well absorbed from the gastrointestinal tract and is rapidly converted into GCV in the intestinal wall and liver. The mechanism of antiviral action is the same that has been described for GCV. All these characteristics make this formulation particularly suitable for the symptomatic congenitally infected newborns. In neonates, V-GCV oral formulation proved stable and constant GVC plasma concentrations, in the suggested therapeutic range. The syrup demonstrated to be clinically effective and well tolerated and to be appropriate for a prolonged post-discharge therapy avoiding the discomfort of hospitalization, reducing the risk for nosocomial infections and decreasing the cost for the National Health Service. This article reviews all the available literature about V-GCV syrup in the treatment of newborns and infants with congenital CMV infection with the regard to pharmacokinetics, pharmacodynamic properties and clinical use, focussing on new data and on our experience.
Clinical and Pharmacological Aspects of Immunoprophylaxis for Respiratory Syncytial Virus Infection in High-Risk Infants by Marcello Lanari, Michela Silvestri, Giovanni A. Rossi (216-225).
Respiratory syncytial virus (RSV) is the leading cause of respiratory tract infection in infants and young children throughout the world. Although preterm birth has been considered for years the major risk factor for severe disease and hospitalization, recent findings indicate that prematurity is not a necessary condition, but one of the independent risk factors for severe RSV infection, together with chronic lung diseases, congenital heart disease and immunodeficiency. Furthermore, over 50% of infants hospitalized for RSV infections during the first year of life are healthy, full-term newborns, suggesting that other environmental and individual factors may be involved. Unfortunately, there is still no specific therapy against RSV infection and therefore prophylactic measures seem to be the only intervention to avoid disease complications. No safe and effective RSV vaccine is available for the prevention of serious RSV infection. Therefore, in addition to hygienic measures, the only approach is passive immunoprophylaxis with humanized monoclonal anti-RSV antibodies, such as palivizumab that have been developed for clinical use. Because of the high cost of these antibodies, a better definition of the individual risk profile for severe RSV infection and timing of administration is needed for optimal effectiveness and careful use of limited health care resources. In this article, we have reviewed the clinical and pharmacological aspects of immunoprophylaxis with monoclonal antibodies for preventing RSV infection in high-risk infants.
Effect of Alpha-1-Acid Glycoprotein Binding on Pharmacokinetics and Pharmacodynamics by Zeqi Huang, Thao Ung (226-238).
Alpha-1-acid glycoprotein (AGP, also known as AAG or orosomucoid) is an important plasma protein involved in the binding and transport of many drugs, especially basic compounds. AGP has some unique drug-binding properties that differ from those of albumin. For example, the plasma concentration of AGP is relatively low and there is only one drug-binding site in each AGP molecule. Thus, binding to AGP is saturable and displaceable. This could have potential implications for drug-drug interactions or toxicological consequences. Furthermore, AGP is an acute phase protein and the concentration of AGP in plasma can significantly increase in various diseases (such as cancer and inflammatory diseases) or following trauma (burns, surgery). Changes in AGP concentration could potentially alter the free fraction of drugs in plasma or at their target sites and eventually affect their pharmacokinetic disposition and pharmacological action. Given that an increasing number of drugs have been shown to bind preferrentially to AGP, a better understanding of this unique interaction may provide great benefit for drug discovery and development. In this review, we will focus on the effect of altered AGP binding on the pharmacokinetics and pharmacodynamics (PK/PD) of drugs, as well as the species differences in AGP binding.
Comparison of P450 Enzymes Between Cynomolgus Monkeys and Humans: P450 Identities, Protein Contents, Kinetic Parameters, and Potential for Inhibitory Profiles by Chie Emoto, Noriaki Yoda, Yasuhiro Uno, Kazuhide Iwasaki, Ken Umehara, Eiji Kashiyama, Hiroshi Yamazaki (239-252).
Cynomolgus monkeys are used to predict human pharmacokinetic and/or toxic profiles in the drug developmental stage. Cynomolgus P450s exhibit a high degree of identity (more than 90%) in both cDNA and amino acid sequences with corresponding human P450s. CYP3A protein predominantly exists in cynomolgus monkey liver microsomes, followed by CYP2A, CYP2C, CYP2B6, CYP2E1, and CYP2D. There are many similarities of metabolic properties in cytochrome P450s between cynomolgus monkeys and humans, but the species differences between cynomolgus monkey and human P450s are clearly present in substrate specificity and inhibitor selectivity. Diclofenac 4'-hydroxylation (DFOH) in monkey liver and intestinal microsomes shows much lower activities compared with those in human liver and intestinal microsomes. Sulfaphenazole strongly inhibits DFOH in human liver microsomes, but does not effectively inhibit DFOH in monkey liver and intestinal microsomes. Cynomolgus CYP2C19 exhibits higher activity for DFOH than cynomolgus CYP2C9 although this reaction is a marker reaction of human CYP2C9. On the other hand, cynomolgus CYP2C76 orthologue is not expressed in humans and shows 70-72% identity in amino acid sequences of human CYP2C subfamilies. Cynomolgus CYP2C76 metabolizes non-CYP2C substrates, 7-ethoxyresorufin (human CYP1A substrate) and bufuralol (human CYP2D6 substrate). In addition, cynomolgus CYP3A4 and CYP3A5 also exhibits wider substrate selectivity toward human CYP2D6 and CYP2E1 substrates. These enzymes may be responsible for species difference in drug metabolism between cynomolgus monkeys and humans. The comparative data presented here can be helpful for designing in vivo metabolic assays using cynomolgus monkeys in terms of substrate specificity and inhibitor selectivity.
An overview of ABC and SLC Drug Transporter Gene Regulation by Qiu-Xia Chen, Hai-Hong Hu, Quan Zhou, Ai-Ming Yu, Su Zeng (253-264).
Membrane transporters play a significant role in drug absorption, distribution and excretion, and they consequently affect the pharmacokinetics, efficacy and safety of a drug. Under certain circumstances, such as pathological processes or exposure to certain substances, the expression of drug transporters is modified in cells. Change in transporter expression and function may affect cellular drug disposition resulting in different drug responses. This raises a number of questions such as which drugs are likely to modulate the expression of drug transporters, what factors support this process, and which transporters are influenced in a particular situation. In this paper, we summarize recent findings to find an answer to these questions. Particularly, we present an overview of the transcription factors involved in the regulation of a given drug transporter, the signaling transduction pathways that contribute to drug transporter gene expression, and xenobiotics and endobiotics that initiate the processes.
Update on Drug Interactions With Phosphodiesterase-5 Inhibitors Prescribed as First-Line Therapy for Patients with Erectile Dysfunction or Pulmonary Hypertension by Serap Gur, Philip J. Kadowitz, Ahmet Gokce, Suresh C. Sikka, Utku Lokman, Wayne J.G. Hellstrom (265-269).
Phosphodiesterase-5 inhibitors (PDE5i, sildenafil, vardenafil, tadalafil and avanafil) are a first-line medical therapy for erectile dysfunction (ED). In all likelihood, PDE5i usage will increase because sildenafil (Viagra® and Revatio®) and tadalafil (Cialis® and Adcirca ®) have recently been recommended as first-line therapy for patients with pulmonary hypertension (PH). PDE5i exhibit higher plasma concentrations when co-administered with cytochrome P (CYP) 3A inhibitors, which influences their side-effect profile. The higher PDE5i plasma concentrations, caused by CYP3A inhibitors, influence the severity and timing of PDE5i drug interactions and require dose adjustment. PDE5i are safe when used with most antihypertensive agents, but co-administration with nitrates or α-blockers can cause severe hypotension and syncope. Dose adjustment is also necessary when PDE5i are co-administered with CYP3A inducers. The combination of oral tadalafil and bosentan (endothelin receptor antagonist) reduces tadalafil levels and requires dose adjustment. Current literature reports a number of interactions between PDE5i and other agents and further studies are needed to expand our knowledge base of these interactions. This review discusses relevant PDE5i drug interactions, including those with CYP 450 inhibitors and inducers which are frequently used during the treatment of ED and PH.