Associative processes disorders in schizophrenia

This paper tries to approach and systematize knowledge about the character of associative process disorders in schizophrenia. In considering schizophrenia as an illness composed of various symptoms which may lead to different clinical progress, the paper is mainly focused on disorganization of thinking and, consequently, speaking and communication disorders. Authors reviewed various concept of pathogenesis and course of associative process disorders in schizophrenic patients. Special attention was paid to a connectionist model of disturbed associations. This model originates from cognitive psychology and assumes that concepts are represented as networks in the mental lexicon. Following from this model, a hypothesis was presented, claiming that disturbed associations in schizophrenia may be related to abnormalities in semantic networks. Results of research, supporting this hypothesis, were referred. Moreover, authors tried to describe the relationship between associative processes disorders in schizophrenia and abnormalities in neurophysiological (event--related potentials) and neuropathological (MRI) examinations. At least hypotheses describing the role of neurotransmission disorders was presented.     

Genetic studies in autistic disorders

Since autism was first described by Leo Kanner the view on its etiology and pathogenesis has been changing. Recently there are more data on genetic and neurobiological background of autism. At the beginning it was noticed that autism appeared more frequently among boys, in population studies it was found that autism appeared more frequently among siblings, mostly among monozygotic twins. Many disorders like Tourett syndrome and tuberous sclerosis were reported in connection with autism. Recently research is focused mostly on chromosome abnormalities: chromosome 15 (locus 15q11-13), chromosome 7 (locus 7q), chromosome 16 (locus 16p) and gens of particular receptors (GABRB3, UBE3A/E6-AP, 5-HTT). These abnormalities may also be one of the causes of autism.     

Absorption and Presystemic Metabolism of Selegiline Hydrochloride at Different Regions in the Gastrointestinal Tract in Healthy Males

Purpose. The absorption and disposition of selegiline (SEL) and its metabolites N-desmethylselegiline (DMS), L-methamphetamine (MET), and L-amphetamine (AMP) were assessed in 8 healthy male volunteers at proximal and distal regions of the intestine relative to oral administration (in the stomach) to determine if intestinal site dependence contributed to the erratic oral absorption of selegiline hydrochloride which is manifest as low and variable bioavailability. Methods. An open-label, four-way crossover, single dose pharmacokinetic study comparing the bioavailability of 10 mg selegiline hydrochloride administered to healthy young males as a solution by the oral route (in the stomach) and by a nasoenteric tube to the following three sites: duodenum, jejunum and terminal ileum was conducted. Infusions were administered over a 1 minute interval and a two week washout was observed between treatments. Samples were taken over 96 hours and analyzed by LC/MS/MS. Results. Selegiline exposure was greatest following administration to the stomach (~150% > duodenum or jejunum) and least in the terminal ileum (~33% less than duodenum or jejunum). Duodenal and jejunal sites were equivocal based on selegiline absorption and subsequent metabolism. While both AMP and MET exposure was equivalent at all dosing sites, DMS exposure was less (~18%) at the terminal ileum. Conclusions. The oral absorption of selegiline is neither permeability-limited or intestinal site-dependent. Stomach absorption may bypass presystemic metabolism. The reduced DMS exposure at the terminal ileum is consistent with the theorized presystemic formation of DMS via luminal P450 enzymes and the density of these enzymes in the duodenum and jejunum relative to the ileum. AMP and MET metabolites were insensitive to dosing site consistent with their hepatic formation. The true magnitude of these effects would require multiple dosing as single dose pharmacokinetics do not predict the extent of multiple dose selegiline exposure.     

Applicability of (SBE)7m-beta-CD in controlled-porosity osmotic pump tablets (OPTs)

The purpose of this study was to investigate the general application of a controlled-porosity osmotic pump tablet (OPT) utilizing (SBE)7m-beta-CD as both a solubilizer and an osmotic agent for drugs with varying physical properties. OPTs utilizing (SBE)7m-beta-CD were prepared for five poorly soluble and two highly water-soluble drugs. The Japanese Pharmacopoeia dissolution method was used to study the drug and (SBE)7m-beta-CD release from the OPTs. The drug concentration in the OPT core after the OPT was placed in the release medium for two hours was assayed gravimetrically and by HPLC. An appropriate composition ratio (ACR) of (SBE)7m-beta-CD to drug at which drug release from the OPT was complete and pH-independent within the physiological pH range of the GI tract was determined for each drug. The ACR values correlate to the drug concentration in the OPT core when the OPTs were placed in the release medium for two hours. The release profiles of prednisolone (a poorly water-soluble drug) and sodium chloride (a water-soluble compound) from the OPTs were almost the same as that of (SBE)7m-beta-CD. Also, the release rate of each drug per unit membrane surface area from the OPTs was similar, regardless of the differences in drug solubility. The present results confirmed that (SBE)7m-beta-CD serves as both a solubility modulator and as an osmotic pumping agent for OPTs, from which the release rate of both water-soluble and poorly water-soluble drugs can be controlled.     

Effect of Cyclodextrin Charge on Complexation of Neutral and Charged Substrates: Comparison of (SBE)7M-β-CD to HP-β-CD

Purpose. To understand the role of charge in substrate/cyclodextrin complexation by comparing the binding of neutral and charged substrates to a neutral cyclodextrin, such as hydroxypropyl –CD (HP––CD) with 3.5 degrees of substitution, and an anionically charged cyclodextrin, such as sulfobutyl ether –CD ((SBE)_7M––CD) with 6.8 degrees of substitution. Method. HP––CD and (SBE)_7M––CD were evaluated in their ability to form inclusion complexes with neutral compounds, as well as to cationic and anionic substrates in their charged and uncharged forms. The complexation constants (K_c) were determined via a UV spectrophotometric technique, by monitoring the change in substrate absorbance upon incremental addition of a concentrated cyclodextrin solution. The role of electrostatic interaction was probed by observing K_c as a function of solution ionic strength. Results. Neutral molecules displayed a stronger interaction with (SBE)_7M––CD compared to HP––CD. In those cases where the guest possessed a charge (positive or negative), HP––CD/substrate complexes exhibited a decrease in complexation strength (2 to 31 times lower) compared to the neutral forms of the same substrate. The same was true (but to a larger extent, 41 times lower) for negatively charged molecules binding to (SBE)_7M––CD due to charge–charge repulsion. However, positively charged molecules interacting with the negatively charged (SBE)_7M––CD displayed a similar binding capability as their neutral counterpart, due to charge–charge attraction. Further evaluation through manipulation of solution ionic strength revealed strong electrostatic interactions between substrate and cyclodextrin charges. In addition, the studies suggested that on average two sulfonates out of seven may be involved in forming ionic attraction or repulsion effects with the positive charges on prazosin and papaverine, or negative charges of ionized naproxen and warfarin. Conclusions. Presence of charge on the cyclodextrin structure provides an additional site of interaction compared to neutral cyclodextrins, which may be modified using solution ionic strength.     

Mechanisms of amine accumulation in, and egress from, lysosomes

The human body is continuously exposed to small organic molecules containing one or more basic nitrogen atoms. Many of these are endogenous (i.e., neurotransmitters, polyamines and biogenic amines), while others are exogenously supplied in the form of drugs, foods and pollutants. It is well-known that many amines have a strong propensity to specifically and substantially accumulate in highly acidic intracellular compartments, such as lysosomes, through a mechanism referred to as ion trapping. It is also known that cells have acquired the unique ability to sense and respond to amine accumulation in lysosomes in an effort to prevent potential negative consequences associated with hyperaccumulation. We describe here methods that are used to evaluate the dynamics of amine accumulation in, and egress from, lysosomes. Moreover, we highlight specific proteins that are thought to play important roles in these pathways. A theoretical model describing lysosomal amine dynamics is described and shown to adequately fit experimental kinetic data. The implications of this research in understanding and treating disease are discussed.     

Cyclodextrins: Their Future in Drug Formulation and Delivery

Pharmaceutical Research - Since their discovery, cyclodextrins and their ability to form inclusion complexes have fascinated chemists, formulators and recently, entrepreneurs. This mini-review has...     

The value of ultrasonography in monitoring limb lengthening]

The authors attempted to assess the value of ultrasound for monitoring of the new bone formation at the site of distraction in patients undergoing limb lengthening after Bastiani. Twenty patients were assessed; 12 cases of femur lengthening and 8 cases of tibia lengthening. It was found, that ultrasound allowed to detect the new bone formation visible as hyperechogenic foci as soon as 4 to 14 days postoperatively, while regular radiology showed this only 4 to 8 weeks after operation. Detection of the new bone formation at the site of lengthening permits, in authors opinion, to choose an optimal onset of distraction and its pace according to the speed of bone formation. Regular ultrasound monitoring prevents premature bone union or disintegration of the newly generated bone in case of to slow or to fast distraction respectively. In two cases sonography early demonstrated cystic changes at the location of distraction. It also permits detection of an axial displacement of the fragments of bone in every case.