Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series

Despite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine, while isoforms 2C19, 2D6, 3A4, and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP's polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and, to a lesser extent, of CYP3A4 and CYP2D6. Hence, in case of CYP's polymorphisms in youth, the use of fluvoxamine as add-on to clozapine could help in reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile as it has already been described in adults. We report four pediatric cases with severe psychiatric disorders underlying our experience with CYP polymorphism explorations and the use of fluvoxamine as add-on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore the clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drug interactions when fluvoxamine is considered. Hence, we propose a detailed step-by-step multidisciplinary protocol.

Interest of Fluvoxamine as an Add-on to Clozapine in Children With Severe Psychiatric Disorder According to CYPs Polymorphisms: Experience From a Case Series

BackgroundDespite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine while isoforms 2C19, 2D6, 3A4 and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP’s polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and to a lesser extent of CYP3A4 and CYP2D6. Hence, in case of CYPs polymorphisms in youth, the use of fluvoxamine as add on to clozapine could help reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile, as it has already been described in adults.Case ReportWe report four pediatric cases with severe psychiatric disorders underlying our experience with CYPs polymorphism explorations and the use of fluvoxamine as add on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drugs interactions when fluvoxamine is considered. Hence, we propose a detailed step by step multidisciplinary protocol.ConlusionThe results pointed out the positive clinical effects of fluvoxamine as add-on to clozapine in youth with severe neurodevelopmental disorders but stresses the need for caution regarding drugs interactions.

Pyranoid Spirosugars as Enzyme Inhibitors

Background: Pyranoid spirofused sugar derivatives represent a class of compounds with a significant impact in the literature. Under the structural point of view, the rigidity inferred by the spirofused entity has made these compound object of interest mainly as enzymatic inhibitors, in particular of carbohydrate processing enzymes among which glycogen phosphorylase and sodium glucose co-transporter 2, important target enzymes for diverse pathological states. Most of the developed compounds present the spirofused entity at the C1 position of the sugar moiety, nevertheless spirofused entities can also be found at other sugar ring positions. The main spirofused entities encountered are spiroacetals/thioacetals, spiro-hydantoin and derivatives, spiro-isoxazolines, spiro-aminals, spiro-lactams, spiro-oxathiazole and spiro-oxazinanone, but also other are present. Objectives: The present review focuses on the most explored synthetic strategies for the preparation of this class of compounds, classified according to the position and structure of the spirofused moiety on the pyranoid scaffold. Moreover, the structures are correlated to their main biological activities or to their role as chiral auxiliaries. Conclusion: It is clear from the review that, among the different derivatives, the spirofused structures at position C1 of the pyranoid scaffold are the most represented and possess the most relevant enzymatic inhibitor activities. Nevertheless, great efforts have been devoted to the introduction of the spirofused entity also in the other positions, mainly for the preparation of biologically active compounds but also for the synthesis of chiral auxiliaries useful in asymmetric reactions; examples of such auxiliaries are the spirofused chiral 1,3-oxazolidin-2-ones and 1,3-oxazolidine-2-thiones.

Fluoride: Its Implications for Public Health

The use of fluoride (F-) for decreasing the prevalence and incidence of tooth decay was the greatest worldwide preventive public health measure of the 20th century. There have been controversial reports about the benefits of the use of F-, because in small amounts it helps prevent dental caries, but in high concentrations it can be potentially toxic and harmful to dental and systemic health. Since the mid-20th century, F- has been studied by toxicologists, looking at its deleterious effects in human populations. During the last decade, the interest on the undesirable effects has resurfaced because of the knowledge that it interacts with the cellular system, even in low doses, with a very small safety margin. Acute ingestion of toxic amounts of fluoride can cause corrosive gastric mucosa injury. Also respiratory effects such as bleeding, pulmonary edema, tracheostomy and shortness of breath, have been observed in individuals who inhale hydrogen fluoride. Some researchers had shown that F- is an oxidizing agent and a well-known reversible enzymatic inhibitor that interferes with the enzyme activity of at least 80 proteins, can altered the intracellular redox equilibrium, lipid peroxidation, as well as, alteration in the gene expression and apoptosis induction. The primary purpose of this review is to examine findings of the action of inorganic F-, and an overview of hard and soft tissue disturbances, known as fluorosis. The goal of this review is to enhance understanding of the mechanisms by which F- affects cells with an emphasis on human tissue-specific events.

Identification of a Small Molecule Inhibitor of the Aminoglycoside 6’-N-Acetyltransferase Type Ib [AAC(6’)-Ib] Using Mixture-Based Combinatorial Libraries

The aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6’)-Ib] is the most widely distributed enzyme among AAC(6’)-I-producing Gram-negative pathogens and confers resistance to clinically relevant aminoglycosides including amikacin. This enzyme is therefore ideal to target with enzymatic inhibitors that could overcome resistance to aminoglycosides. The search for inhibitors was carried out using mixture-based combinatorial libraries, the scaffold ranking approach, and the positional scanning strategy. A library with high inhibitory activity had pyrrolidine pentamine scaffold and was selected for further analysis. This library contained 738,192 compounds with functionalities derived from 26 different amino acids (R1, R2 and R3) and 42 different carboxylic acids (R4) in four R group functionalities. The most active compounds all contained S-phenyl (R1 and R3) and S-hydromethyl (R2) functionalities at three locations and differed at the R4 position. The compound containing 3-phenylbutyl at R4 (compound 206) was a robust enzymatic inhibitor in vitro, in combination with amikacin potentiated the inhibition of growth of three resistant bacteria in culture, and improved survival when used as treatment of Galleria mellonella infected with aac(6’)-Ib-harboring Klebsiella pneumoniae and Acinetobacter baumannii strains.

Biochemical detection of E-ADA on Neospora caninum tachyzoites and the effects of a specific enzymatic inhibitor

Objective. This study aimed to investigate the presence and activity of the ecto adenosine deaminase (E-ADA) enzyme in tachyzoites of Neospora caninum (Nc-1 strain), as well as to assess the activity of a well-known E-ADA inhibitor, the deoxycoformycin. Materials and methods. The parasites were grown in cell culture, being subsequently separated in a pellet of tachyzoites, on which the E-ADA activity was tested using the concentrations 0 (control), 0.2, 0.4 and 0.8 mg mL-1. Results. The E-ADA showed high activity, progressively increasing its activity according to the enhancement of the protein concentration. The test was carried out with different concentrations of deoxycoformycin, showing that it was able to inhibit the E-ADA present on the free form of the parasite. Conclusions. Based on these results we conclude that the E-ADA is present on tachyzoites of N. caninum, and deoxycoformycin is able to inhibit this enzyme. In this sense, knowing the negative impact of N. caninum on reproductive issue in cattle (mainly abortion), might it is an alternative in order to deal with this parasitic infection.Key words: adenosine deaminase, deoxycoformycin, neosporosis (Source: CAB, MeSH).