Patients' perspective on their drug therapy after bariatric surgery: A quantitative, cross-sectional interview study.

Drug therapy in patients who have undergone bariatric surgery is challenging. We aimed to investigate the patients' perspective on their drug therapy. This should allow deriving tailored measures to better support patients and their healthcare professionals with drug therapy after bariatric surgery. We conducted a quantitative telephone-based interview study with patients who have undergone bariatric surgery. The interview consisted of assessments in three parts: (i) current drug therapy: prescription, administration and adherence, (ii) changes after bariatric surgery and (iii) adverse events. (i) The 105 enrolled patients were taking a median of 10 (range: 3-30) drugs. In 1017 of 1080 drugs (94%), expectations in drug effectiveness were (rather) met. Of the 105 patients, 27% reported difficulties in drug administration, 44% forgot to take their drugs at least one time and 20% reported deviations from the prescription. (ii) Sixteen percent of the patients observed changes in drug effectiveness or tolerability-additionally to therapy adjustment by physicians. (iii) Seventy-four percent recognised at least one adverse event right before and/or after bariatric surgery, most frequently in gastrointestinal disorders. Patients who have undergone bariatric surgery have to deal with many difficulties in drug handling and adverse events. Our study emphasises the need for better and more individual support for patients with their drug therapy after bariatric surgery and, therefore, suggests a multidisciplinary approach that includes pharmacists. The stronger involvement of the patients' perspective seems to be a valuable source in research and practice.

Developmental impairments of select neurotransmitter systems in brains of Cln3(Deltaex7/8) knock-in mice, an animal model of juvenile neuronal ceroid lipofuscinosis.

The neuronal ceroidlipofuscinoses (NCL) are a group of neurodegenerative disorders and are the most common lysosomal storage diseases of infancy and childhood. Juvenile NCL is caused by CLN3 mutation, producing retinal degeneration, uncontrollable seizures, cognitive and motor decline, and early death before the age of 30 years. To study the pathogenetic mechanisms of the disease, Cln3 knock-in mice (Cln3(Deltaex7/8)) have been generated, which reproduce the 1.02-kb deletion in the CLN3 gene observed in more than 85% of juvenile NCL patients. To characterize the impact of the common Cln3 mutation on development of autofluorescent storage material, gliosis, glucose metabolism, oxidative stress, and transmitter receptors during postnatal brain maturation, brain tissue of Cln3(Deltaex7/8) mice at the ages of 3, 4, 5, 6, 9, and 19 months was subjected to immunocytochemistry to label gliotic markers and nitric oxide synthases; photometric assays to assess enzyme activities of glycolysis and antioxidative defense systems; and level of reactive nitrogen species as well as quantitative receptor autoradiography to detect select cholinergic, glutamatergic, and GABAergic receptor subtypes. The developmental increase in cerebral cortical autofluorescent lipofuscin-like deposition is accompanied by a significant astro- and microgliosis, increased activities of lactate dehydrogenase and phosphofructokinase, decreased level of glutathione peroxidase, enhanced amount of reactive nitrogen species, and lowered binding levels of N-methyl-D-aspartate- and M1-muscarinic acetylcholine receptors in select brain regions but hardly in GABA(A) receptor sites compared with wild-type mice. Detailed elucidation of the sequence of pathological events during postnatal development highlights new potential strategies for symptomatic treatment of the disease.

beta-Amyloid deposition and prion infection in adult primary brain cell long-term culture model.

We report an in vitro model of the adult central nervous system produced by culturing primary brain cells isolated from adult mice for periods longer than 4 months. We applied this novel cell culture method to model progressive neurodegenerative diseases. After long-term culture of adult primary brain cells prepared from Alzheimer's disease and prion disease mouse models, we observed beta-amyloid deposition and prion infection in primary cell cultures in vitro.

Toxicity mediated by soluble oligomers of beta-amyloid(1-42) on cholinergic SN56.B5.G4 cells.

Alzheimer's disease (AD) is characterized by cholinergic dysfunction and progressive basal forebrain cell loss which has been assumed to be as a result of the extensive accumulation of beta-amyloid (Abeta). In addition to Abeta fibrillar assemblies, there are pre-fibrillar forms that have been shown to be neurotoxic, although their role in cholinergic degeneration is still not known. Using the cholinergic cell line SN56.B5.G4, we investigated the effect of different Abeta(1-42) aggregates on cell viability. In our model, only soluble oligomeric but not fibrillar Abeta(1-42) forms induced toxicity in cholinergic cells. To determine whether the neurotoxicity of oligomeric Abeta(1-42) was caused by its oxidative potential, we performed microarray analysis of SN56.B5.G4 cells treated either with oligomeric Abeta(1-42) or H(2)O(2). We showed that genes affected by Abeta(1-42) differed from those affected by non-specific oxidative stress. Many of the genes affected by Abeta(1-42) were present in the endoplasmic reticulum (ER), Golgi apparatus and/or otherwise involved in protein modification and degradation (chaperones, ATF6), indicating a possible role for ER-mediated stress in Abeta-mediated toxicity. Moreover, a number of genes, which are known to be involved in AD (clusterin, Slc18a3), were identified. This study provides important leads for the understanding of oligomeric Abeta(1-42) toxicity in cholinergic cells, which may account in part for cholinergic degeneration in AD.

Structural changes of benzylether derivatives of vesamicol and their influence on the binding selectivity to the vesicular acetylcholine transporter.

18F labelled vesamicol analogues, which bind to the vesicular acetylcholine transporter (VAChT) in central cholinergic nerve terminals, are expected to be potential radioligands for the visualisation of cholinergic transmission deficits via positron emission tomography (PET). In this report the regioselective synthesis of five novel vesamicol analogues as well as their in vitro binding properties to the VAChT are described. Beside having the 4-fluorobenzylether-substitution at the cyclohexyl ring as an unique structural feature, the new compounds are additionally modified at the phenyl and piperidine moiety of the vesamicol skeleton. The affinity and selectivity to the VAChT were analysed by competitive binding studies using tritium labelled radioligands. The VAChT affinities (Ki-values) of the novel compounds were estimated ranging between 7.8+/-3.5 nM and 161.6+/-17.3 nM, thus some of them are binding with higher affinity to the transporter than vesamicol. However, the compounds tested demonstrated also affinities to the sigma receptors sigma1 and sigma2 ranging between 4.1+/-1.5 nM and 327.5+/-75.9 nM. Nevertheless, these data provide the basis for future structure-binding-studies and further underline the potential and usefulness of vesamicol analogues for imaging of the VAChT.

Synthesis of novel 4- and 5-substituted benzyl ether derivatives of vesamicol and in vitro evaluation of their binding properties to the vesicular acetylcholine transporter site.

Detection of the central cholinergic deficits, a consistent feature of Alzheimer's disease, is essential to allow preventive measures and/or symptomatic treatment already at a very early stage of the disease. The vesicular acetylcholine transporter (VAChT) represents an appropriate target to establish PET radiotracer that are adequate for brain imaging the loss of cholinergic terminals. Here we describe the synthesis and binding characteristics of novel derivatives of vesamicol, known to represent a specific antagonist of VAChT sites. Novel benzyl ether derivatives of vesamicol either 4- or 5-substituted at the cyclohexylring have been synthesized by different regioselective ring opening reactions of a same epoxide precursor. The affinity and selectivity of the novel compounds to VAChT sites were analyzed by competitive radioligand binding studies in rat brain and liver membrane preparations using tritium labeled radioligands. The 4-substituted fluorobenzylether of vesamicol 10b was shown to exhibit a high affinity to VAChT sites (K(i)-value(10b)=10.7+/-1.7 nM), but demonstrated also binding capacities to sigma receptors (K(i-)value(10b)=18.5+/-6.9 nM, [(3)H]DTG; K(i)-value(10b)=30.6+/-9.6 nM, [(3)H]haloperidol). The data suggest the potential of vesamicol derivatives to design appropriate radiotracer for PET imaging of central cholinergic deficits.