Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Inhibition of synaptosomal uptake of amino acid transmitters by diamines

Reports of the inhibitory effects of diaminocarboxylic acids on the uptake of amino acid transmitters led the present authors to examine the effects of simple aliphatic diamines on the synaptosomal uptake of glutamate, aspartate, GABA and glycine. The diamines studied were the series from ethylenediamine through to 1,7-diaminoheptane; DL-2,4-diaminobutyric acid (DABA) was also tested for comparative purposes. The greatest inhibition seen was on the uptake of glycine and GABA. Weaker effects on uptake were seen with glutamate, while aspartate was unaffected. The patterns of inhibition for glycine and GABA were similar and the effects were dose-dependent. 1,2-Diaminopropane was the most inhibitory, followed by ethylenediamine and 1,7-diaminoheptane. The reported inhibitory effects of DL-2,4-diaminobutyric acid on the uptake of GABA and glutamate were confirmed; comparable inhibition of the uptake of glycine and aspartate was seen but the effects on GABA were most potent. Inhibition of the uptake of GABA by 1,2-diaminopropane was approximately one fifteenth that reported for DL-2,4-diaminobutyric acid. The inhibition by diamine of the uptake of glycine and GABA can provide an explanation of the depressant effects of diamines, seen after ventricular administration; however, the excitotoxic effects of the diamines 1,3-diaminopropane through to 1,7-diaminoheptane could not be explained by the present results.     

Inhaled therapeutics for prevention and treatment of pneumonia

The lungs are the most common site of serious infection owing to their large surface area exposed to the external environment and minimum barrier defense. However, this architecture makes the lungs readily available for topical therapy. Therapeutic aerosols include those directed towards improving mucociliary clearance of pathogens, stimulation of innate resistance to microbial infection, cytokine stimulation of immune function and delivery of antibiotics. In our opinion inhaled antimicrobials are underused, especially in patients with difficult-to-treat lung infections. The use of inhaled antimicrobial therapy has become an important part of the treatment of airway infection with Pseudomonas aeruginosa in cystic fibrosis and the prevention of invasive fungal infection in patients undergoing heart and lung transplantation. Cytokine inhaled therapy has also been explored in the treatment of neoplastic and infectious disease. The choice of pulmonary drug delivery systems remains critical as air-jet and ultrasonic nebulizer may deliver sub-optimum drug concentration if not used properly. In future development of this field, we recommend an emphasis on the study of the use of aerosolized hypertonic saline solution to reduce pathogen burden in the airways of subjects infected with microbes of low virulence, stimulation of innate resistance to prevent pneumonia in immunocompromised subjects using cytokines or synthetic pathogen-associated molecular pattern analogues and more opportunities for the use of inhaled antimicrobials. These therapeutics are still in their infancy but show great promise.     

Recommandations de bon usage des carbapénèmes

Carbapenems are being increasingly used because of the widespread dissemination of antibiotic resistance among Gram-negative bacilli, especially of extended-spectrum beta-lactamases; this increasing use raises the concern of loss of activity for this antimicrobial class following the emergence of carbapenemases. The current guideline from the Anti-infective drugs Committee of the Assistance publique-Hôpitaux de Paris (AP–HP) group emphasizes the careful and limited use of carbapenems, comparing the respective characteristics of the four available molecules, and specifies their indications in clinical hospital practice, with possible alternatives.     

Antifungal drugs in pregnancy: a review

The use of any medication in pregnant women requires careful consideration of benefit to the mother versus risk posed to the fetus. Fungal infections are not uncommon in pregnant women; in fact, the incidence of certain infections such as Candida vaginitis is increased in this patient population. A variety of antimycotic agents are currently available to treat systemic or mucocutaneous fungal infections. Many of these agents are capable of penetrating the placental barrier and entering fetal cord blood, therefore adverse effects of these agents on the fetus are a valid concern. The use of topical azoles for the treatment of superficial fungal infections is safe and efficacious. However, there are some data suggesting a dose-related increase in the risk of teratogenicity associated with the use of systemic azoles. Amphotericin B remains the drug of choice for the treatment of systemic fungal infections in pregnancy. There are serious risks of fetal malformations associated with the use of griseofulvin, ketoconazole, voriconazole, flucytosine and potassium iodide. These drugs are contraindicated in pregnancy. There are insufficient data regarding the use of caspofungin in pregnancy. This article will review available data regarding the safety of antifungal drug use in pregnant women.     

RELATIONSHIP BETWEEN GASTRIC MUCUS SYNTHESIS, SECRETION AND SURFACE GEL EROSION MEASURED IN AMPHIBIAN STOMACH IN VITRO

1. The layer of adherent mucus that protects the surface of the stomach reflects a dynamic balance between biosynthesis of glycoprotein, secretion of preformed mucus and erosion of the adherent gel layer. The present study is the first in which all these processes have been measured concomitantly and was undertaken to define interrelationships between the three parameters. 2. A chambered sac preparation of amphibian gastric mucosa is described. Biosynthesis was determined by specific incorporation of radiolabeled sugars into purified glycoprotein. Mucus secretion was determined by measuring the thickness of the adherent gel and erosion of the surface layer was assessed from the appearance of soluble mucin in the luminal solution. 3. 16,16-Dimethyl-prostaglandin (PG. E₂ stimulated glucosamine incorporation by 10-fold, but did not alter the rate of incorporation of galactose. There was a rapid two-fold increase in the thickness of the adherent mucus layer but no change in the rate of erosion. Dibutyryl-cAMP also stimulated mucus release but, unlike PG, increased glycoprotein labelling by galactose. 4. Both distention or the application of a cholinergic agonist increased adherent mucus thickness. Stimulation of mucus release in response to carbachol was accompanied by a decrease in glycoprotein labelling by galactose. In contrast, the adrenergic agent noradrenaline decreased secretion but did not influence labelling. 5. These results indicate that biosynthesis and secretion of gastric mucus are subject to differential regulation. Moreover, the profile of incorporation of sugars in response to secreta-gogues also differs, indicating the need for caution when interpreting effects on glycoprotein biosynthesis.     

SIZE-DEPENDENT RELEASE OF CARBOXYFLUORESCEIN FROM CETYLMANNOSIDE-MODIFIED LIPOSOMES IN HUMAN PLASMA

The interaction of liposomes with human plasma was investigated using 6(5)-carboxyfluorescein (CF) as an aqueous phase marker of cetylmannoside-modified multilamellar vesicles (Man-MLVs) of various sizes. The release of CF decreased with increasing liposome concentration. The time courses of the CF release from Man-MLVs were monitored continuously and were analysed kinetically. The curves were characterized by two phases, the first-order release process and the maximum release, which represent the rate and the extent of CF release, respectively. The increase of liposome size increased the rate of release by 42% and the extent of release by 121%, respectively. These effects of liposome size on the release processes were suggested to result from the size-dependent affinities of liposomes to the human complement system. The assay system of liposomally bound fragments of complement component 3 (C3), such as C3b and/or iC3b, was developed by applying a sandwich enzyme-linked immunospecific assay. The percentage of C3 fragments to total proteins bound to liposomes increased with the size of liposomes and there was a good correlation between the extent of CF release and the percentage of C3 fragments bound. These results indicated that Man-MLVs released entrapped CF via activating the human complement system and the affinity of Man-MLV to complement increased with the size of Man-MLVs in human plasma. These in vitro results suggest the role of complement as an opsonin in the disposition of Man-MLVs in humans.     

Bioavailabilities of rectal and oral methadone in healthy subjects

AIMS: Rectal administration of methadone may be an alternative to intravenous and oral dosing in cancer pain, but the bioavailability of the rectal route is not known. The aim of this study was to compare the absolute rectal bioavailability of methadone with its oral bioavailability in healthy humans. METHODS: Seven healthy subjects (six males, one female, aged 20-39 years) received 10 mg d(5)-methadone-HCl rectally (5 ml in 20% glycofurol) together with either d(0)-methadone intravenously (5 mg) or orally (10 mg) on two separate occasions. Blood samples for the LC-MS analyses of methadone and it's metabolite EDDP were drawn for up to 96 h. Noninvasive infrared pupillometry was performed at the same time as blood sampling. RESULTS: The mean absolute rectal bioavailability of methadone was 0.76 (0.7, 0.81), compared to 0.86 (0.75, 0.97) for oral administration (mean (95% CI)). Rectal absorption of methadone was more rapid than after oral dosing with Tmax values of 1.4 (0.9, 1.8) vs. 2.8 (1.6, 4.0) h. The extent of formation of the metabolite EDDP did not differ between routes of administration. Single doses of methadone had a duration of action of at least 10 h and were well tolerated. CONCLUSIONS: Rectal administration of methadone results in rapid absorption, a high bioavailability and long duration of action. No evidence of presystemic elimination was seen. Rectal methadone has characteristics that make it a potential alternative to intravenous and oral administration, particularly in cancer pain and palliative care.