be related to the downregulation of

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What contributes to the sensitivity of microalgae to triclosan?

Differential sensitivities of microalgae to triclosan have been reported, which may have significant implications for environmental risk assessment of this widely used biocide. Therefore, the aim of this study was to derive a mechanistic understanding of varying microalgal sensitivity to this substance. The toxicity of triclosan was evaluated using microalgal systems varying in biological complexity, exposure time and systematic position (a synchronized culture of the chlorophyte Scenedesmus vacuolatus, a diatom Nitzschia palea cultivated in suspension as well as attached to surfaces and periphyton communities). The results revealed (1) differences in sensitivity of the selected microalgal systems of three orders of magnitude and (2) highest sensitivity of the chlorophyte to triclosan in the range of environmental concentrations. To investigate algal sensitivity to triclosan in more detail, bioavailability was considered by investigating suspended and attached living algae. Differences in the generation time (in comparison to test duration) of the species were addressed by evaluating and modeling concentration-time-effect relationships. However, varying sensitivities of the selected microalgal systems remained unexplained. Comparison of species-specific toxic responses to calculated effect concentrations, derived from quantitative relationships for narcosis and uncoupling mode-of-action, leads us to the conclusion that triclosan may address multiple target sites in different microalgal species.     

Drug transfer to the fetus and to the breastfeeding infant: what do we know?

The pregnant patient with inflammatory bowel disease presents a number of challenges to the clinician. In addition to the management of the patient's disease activity and the potential effects of disease on pregnancy, the clinician must also take into consideration any iatrogenic complications that may arise from the medical management of these conditions. Furthermore, should the patient elect to breastfeed her infant, the effect of drugs that may be passed through the breast milk must also be considered. This article focuses specifically on the issues of drug transfer to the fetus and to the breastfeeding infant. Meperidine is the sedative of choice for endoscopic procedures on pregnant patients, while benzodiazepines and propofol may be used with certain caveats. Amoxicillin/clavulanic acid and metronidazole are preferred if antibiotics are indicated for perianal Crohn's disease or pouchitis. The majority of medications used in the treatment of luminal IBD in pregnancy are not associated with significant adverse effects, and thus can generally be used safely. Certain medications, such as aminosalicylates, corticosteroids, and cyclosporine, appear low risk, while others such as methotrexate and thalidomide are clearly contraindicated. The role of other immunomodulators and biologics remains to be clearly defined, although early experience with infliximab and similar agents appear to be low risk. Safety in breastfeeding varies considerably among medications. There are many issues to address when considering pharmaceutical intervention in the pregnant patient, and patients should be carefully counseled regarding potential teratogenicity or adverse outcomes of medication used during pregnancy and breastfeeding.     

G-protein βγ-subunits contribute to the coupling specificity of the β2-adrenergic receptor to Gs

Receptors and heterotrimeric G-proteins interact with a high degree of specificity, the molecular basis of which is only partially understood. In the present study, we analyzed the influence of different G-protein betagamma-subunits on the coupling of the beta2-adrenergic receptor to G(s). Sf9-cells were infected with baculoviruses coding for the beta2-adrenergic receptor, alpha(s,Short) or alpha(s,Long), and various beta- and gamma-subunits. The ability of different beta- and gamma-subunits to correctly dimerize was assessed by limited proteolysis of proteins expressed in Sf9-cells and additionally by analysis of beta/gamma-interaction in the yeast two-hybrid system. Agonist-induced GTPgammaS-binding to alpha(s,Short)beta(1)gamma-trimers was significantly higher than to alpha(s,Short)beta2gamma-combinations, when gamma4, gamma5, or gamma7 were co-expressed. Because beta(5) did not support coupling of the beta(2)-adrenergic receptor to G(s), the 87 C-terminal amino acids of Gbeta(5) assumed to encompass the beta-subunit interface with the receptor were substituted by the corresponding sequence of beta(1). Whereas this beta(5)/beta(1)-chimera did not promote GTPgammaS-binding to alpha(s), histamine H(1)-receptor-dependent GTPgammaS-binding to alpha(q) was supported by this chimeric beta-subunit and by wild-type beta(5). Our findings argue that the betagamma-subunit composition contributes directly to the specificity of beta(2)-adrenergic receptor-mediated G(s)-activation.     

Methadone maintenance treatment: is it possible to adapt the daily doses to the metabolic activity of the patient?

Controversy still exists concerning the proper daily dose of methadone to be used in opiate dependency treatment. Because it is admitted that serum methadone concentration may be significantly correlated with the amount of drug available at the receptor level, it could be interesting to predict the methadone daily doses necessary to reach such a serum concentration. The authors have attempted to correlate the serum methadone level with the daily intake, considering the metabolic activity of the patients. A poor correlation was found between methadone doses and methadone serum concentrations (r2 = 0.0409, p = 0.048). The test used to determine the metabolic activity of patients is the 6-OH cortisol/17-OH corticosteroids ratio in urine. This urinary 6-OH cortisol/17-OH corticosteroids ratio was tested because cortisol is metabolized through the same P450 cytochromes as methadone, namely cytochrome P450 3A4. This determination could be of interest because it could be tested before methadone administration to predict optimal doses. But when the authors tried to correlate the methadone serum concentration with the steroid ratio, they failed to find a significant correlation (r2 = 0.0046, N.S.), even when they took into account the daily doses (r2 = 0.0015, N.S.), most probably because of some limitations of the cortisol ratio.     

Dyslipidaemia in the elderly: to treat or not to treat?

Introduction: The elderly population (i.e. aged ≥ 65 years) is increasing worldwide. Ageing is associated with a higher incidence and prevalence of cardiovascular disease (CVD).

Areas covered: The prevalence of CVD risk factors including type 2 diabetes mellitus, hypertension and dyslipidaemia also increases with advancing age, contributing to the higher absolute CVD risk observed in the elderly. The present narrative review comments on the associations of dyslipidaemia with CVD as well as the effects of lifestyle measures and lipid-lowering drugs on lipids and CVD risk with a special focus on the elderly population. Individual treatment goals and therapeutic options according to current guidelines are also reviewed. Finally, we discuss special characteristics of the elderly that may influence the efficacy and safety of drug therapy and should be considered before selection of hypolipidaemic pharmacotherapy.

Expert commentary: There may be a greater CVD benefit in older patients following drug therapy compared with younger ones. Treatment goals and therapeutic options should be individualized according to current guidelines. Specific characteristics that may influence the efficacy and safety of drug therapy in the elderly should be considered in relation to dyslipidaemia treatment.     

Hydrogen sulfide: from the smell of the past to the mediator of the future?

Gases such as nitric oxide and carbon monoxide play important roles both in normal physiology and in disease. In recent years, interest has been directed towards other naturally occurring gases, notably hydrogen sulfide (H₂S), which is both a potent vasodilator and a mediator of long-term potentiation in the brain. This article focuses on recent work that suggests a role for H₂S, and perhaps other gases, in the CNS and cardiovascular system.     

Altering the way the optic nerve head responds to intraocular pressure—a potential approach to glaucoma therapy

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Highlights► Optic nerve head biomechanics influences the relationship between IOP and glaucoma. ► A ‘stiffer’ sclera reduces ganglion cell loss in an animal model of glaucoma. ► Sclera stiffens with ageing and glaucoma increases with age. ► It is theoretically possible to cross-link sclera to increase its stiffness. ► Unclear whether scleral cross-linking will be safe or protective in glaucoma.     

Approaches to the pharmacological treatment of obesity

Obesity is a global health crisis resulting in major morbidity and premature death. The need for safe and efficacious drug therapies is great, and presently unmet. The two drugs currently licensed in the USA for the long-term treatment of obesity, orlistat and sibutramine, provide only modest weight-loss benefits and are associated with high attrition rates owing to side effects. This review summarizes current concepts in the neuroendocrine control of energy homeostasis and major pharmacological treatments for obesity in the pipeline.     

Facing up the ROS labyrinth--Where to go?

Evidence indicates that oxidative stress refers to a condition where cells are subjected to excessive levels of reactive oxygen species (ROS). Overall vascular function is dependent upon a fine balance between oxidant and antioxidant mechanisms which is required, at least in part, for proper functioning of the endothelium. Considerable experimental and clinical data indicate that the intracellular oxidant milieu is also involved in several redox-sensitive cellular signaling pathways, such as ion transport systems, protein phosphorylation, and gene expression and thus also plays important roles as modulator of vascular cell function, such as cell growth, apoptosis, migration, angiogenesis and cell adhesion. Overproduction of ROS under pathophysiologic conditions is integral in the development of vascular disease. This fact stimulated an intensive search of new pharmacological approaches to improve vascular hemeostasis and, particularly those intended to decrease oxidative stress or augment the antioxidant defense mechanisms.     

Scopolamine prevents the development of sensitization to morphine

AIM : The repeated use of opiates in humans has been associated with progressive enhancement of anxiety, panic attacks, and eventually paranoid psychosis. The appearance of such behaviors has been termed behavioral sensitization,which forms part of the basic pathological mechanisms involved in drug addiction. Muscarinic cholinergic receptors of the