Cortical thickness across the cingulate gyrus in schizophrenia and its association to illness duration and memory performance.

Schizophrenia has been associated with structural brain abnormalities and cognitive deficits that partly change during the course of illness. In the present study, cortical thickness in five subregions of the cingulate gyrus was assessed in 44 patients with schizophrenia-spectrum disorder and 47 control persons and related to illness duration and memory capacities. In the patients group, cortical thickness was increased in the posterior part of the cingulate gyrus and related to illness duration whereas cortical thickness was decreased in anterior parts unrelated to illness duration. In contrast, cortical thickness was related to episodic and working memory performance only in the anterior but not posterior parts of the cingulate gyrus. Our finding of a posterior cingulate increase may point to either increased parietal communication that is accompanied by augmented neural plasticity or to effects of altered neurodegenerative processes in schizophrenia.

Attenuated prefrontal activation during decision-making under uncertainty in schizophrenia: a multi-center fMRI study.

Decisions are called decisions under uncertainty when either prior information is incomplete or the outcomes of the decision are unclear. Alterations in these processes related to decisions under uncertainty have been linked to delusions. In patients with schizophrenia, the underlying neural networks have only rarely been studied. We aimed to disentangle the neural correlates of decision-making and relate them to neuropsychological and psychopathological parameters in a large sample of patients with schizophrenia and healthy subjects. Fifty-seven patients and fifty-seven healthy volunteers from six centers had to either indicate via button-press from which of two bottles red or blue balls were drawn (decision-making under uncertainty condition), or indicate whether eight red balls had been presented (baseline condition) while BOLD signal was measured with fMRI. Patients based their decisions on less conclusive evidence and had decreased activations in the underlying neural network, comprising of medial and lateral frontal as well as parietal areas, as compared to healthy subjects. While current psychopathology was not correlated with brain activation, positive symptoms led to longer decision latencies in patients. These results suggest that decision-making under uncertainty in schizophrenia is affected by a complex interplay of aberrant neural activation. Furthermore, reduced neuropsychological functioning in patients was related to impaired decision-making and task performance was modulated by distinct positive symptoms.

Investigation of decision-making under uncertainty in healthy subjects: a multi-centric fMRI study.

Decision-making is an everyday routine that entails several subprocesses. Decisions under uncertainty occur when either prior information is incomplete or the outcomes of the decision are unclear. The aim of the present study was to disentangle the neural correlates of information gathering as well as reaching a decision and to explore effects of uncertainty acceptance or avoidance in a large sample of healthy subjects. Sixty-four healthy volunteers performed a decision-making under uncertainty task in a multi-center approach while BOLD signal was measured with fMRI. Subjects either had to indicate via button press from which of two bottles red or blue balls were drawn (decision-making under uncertainty condition), or they had to indicate whether 8 red balls had been presented (baseline condition). During the information gathering phase (contrasted against the counting phase) a widespread network was found encompassing (pre-)frontal, inferior temporal and inferior parietal cortices. Reaching a decision was correlated with activations in the medial frontal cortex as well as the posterior cingulate and the precuneus. Effects of uncertainty acceptance were found within a network comprising of the superior frontal cortex as well as the insula and precuneus while uncertainty avoidance was correlated with activations in the right middle frontal cortex. The results depict two distinct networks for information gathering and the indication of having made a decision. While information-gathering networks are modulated by uncertainty avoidance and - acceptance, underlying networks of the decision itself are independent of these factors.

Release of gentamicin sulphate from biodegradable PLGA-implants produced by hot melt extrusion.

For a long-term local treatment of osteomyelitis biodegradable poly(lactic-co-glycolic acid) (PLGA) implants loaded with gentamicin sulphate (GS) were prepared, analysed and compared to the marketed product Septopal (Biomet, Darmstadt, Germany), which consists of polymethylmethacrylate (PMMA) beads loaded with the same active ingredient. The implants were manufactured by hot melt extrusion with a twin screw extruder. In order to decrease the processing temperature and to improve the drug release behaviour, polyethylene glycol 400 (PEG 400) was added as plasticizer in different concentrations. The glass transition temperature of PLGA measured by differential scanning calorimetry declined in the same manner as the extrusion temperature with increasing PEG 400 concentration. The extrudates of all batches exhibited good encapsulation efficiency between 85% and 115% of the specified content. The behaviour of the implants during exposure to a release medium were characterised by scanning electron microscopy, gravimetric analysis and finally in vitro drug release studies. The results suggest that drug liberation is not affected by the addition of PEG 400, and depends on the drug-PLGA ratio only. Extrudates with 25% GS showed a release pattern with an initially higher drug release followed by a zero order kinetic for about four weeks and showed release profiles equivalent to Septopal.

A new formulation concept for drugs with poor water solubility for parenteral application.

The parenteral application of active substances with poor solubility in water is often bound to the use of stabilizing excipients or surfactants with serious undesired side effects. A new concept is introduced based on a drug concentrate, comprising the active substance dissolved in parenterally acceptable organic solvents, and an aqueous dilution medium, which are mixed in a special mixing device immediately prior to application and thus generating the applicable formulation directly prior to administration. Due to the requirement of formulation stability for only a few minutes, the amount of stabilizing agents can be reduced significantly. It can be shown that model drugs dissolved in a mixture of polyoxyethylen glycol, ethanol and soya lecithin as stabilizer may be mixed to an aqueous glucose solution resulting in a parenterally acceptable and administerable dispersion which is physically stable for several minutes. First in vivo data show good tolerability and blood plasma levels which are comparable to conventional solutions.

The intensity dependence of auditory evoked ERP components predicts responsiveness to reboxetine treatment in major depression.

INTRODUCTION: The intensity (loudness)-dependent amplitude change (IDAP) of auditory evoked event-related potential (ERP) components has been suggested as an indicator of central serotonergic neurotransmission. In patients with major depression, associations of high IDAP with favorable SSRI treatment outcome have been reported. This is the first study to assess the predictive value of the IDAP in SNRI treatment. METHODS: We evaluated the pre-treatment intensity-dependent change of auditory evoked P1, N1, P2, and P1/N1 and N1/P2 peak-to-peak amplitudes in 14 inpatients with major depressive episode (DSM IV) in the course of 24 days of treatment with the SNRI reboxetine (6-12 mg/d). RESULTS: Our data revealed a highly significant correlation between lower intensity-dependent N1 amplitude slopes prior to reboxetine treatment and stronger decrease of HDRS total score at Fz ( r = 0.86, P < 0.001), Fcz ( r = 0.91, P < 0.001), and Cz ( r = 0.93, P < 0.001). CONCLUSION: This result corroborates the hypothesis of the IDAP as a differential indicator of serotonergic versus noradrenergic antidepressant psychopharmacotherapy.

Partial solubility parameters of poly(D,L-lactide-co-glycolide).

During production of microparticles by the polymer incompatibility method a polymer solution is demixed. Therefore, investigations into solubility are often carried out when the suitability of a polymer is examined. Solubility parameters can be used to quantify the solubility. For polylactide and polyglycolide as commonly employed copolymers for microparticles the solubility parameters have rarely been documented. This study aimed to determine solubility parameters and partial solubility parameters for different proportions of lactide to glycolide for poly(D,L-lactide-co-glycolide) (PLGA). The employed methods were compared and solubility maps established. Finally the accuracy of the results was discussed for different polymer batches which were used for production of microparticles. Although the turbidity titration method was found to be the most precise, it was not possible to sufficiently explain the differences between three polymer batches during microparticle production.

Parameters with influence on the droplet size of w/o emulsions.

The aim of this study was to show that for w/o emulsions a modulation of components and parameters is necessary. Therefore several w/o emulsions were produced according to a 2(4) factorial design to get the information that pressure and temperature as production parameter have less influence on the droplet size than the substance components olive oil and lecithin. Furthermore an interaction between surfactant and oil component was observed which resulted in an increase of droplet size. With the following experiments the interfacial tension and the viscosity as physicochemical parameters were determined but gave no explanation for the phenomenon of an increasing droplet size if olive oil and lecithin are part of the formulation. So the influence of substance components was examined in more detail with the successive addition of oleic acid or oleyl alcohol to MCT and due to this the presence of unsaturated substances in olive oil could be determined as a possible reason for interactions with lecithin.

Lyoprotection of aviscumine with low molecular weight dextrans.

The aim of this research was to ascertain whether dextrans with low molecular weight will stabilize aviscumine. During freeze-drying increasing concentrations of dextran T1 (MW 1000) stabilized aviscumine. Eight percent of dextran resulted in a nearly 100% recovery of the activity and in addition a complete amorphous structure of the solid phase was obtained. By decreasing the molecular weight of the dextran from 75 to 1 kDa, the protein activity was increased by 20% in the lyophilisate. Combinations of dextran with either trehalose or mannitol showed no additional effects on stability. The improved stabilization of aviscumine using low molecular weight dextrans is explained by an increased interaction between the protein and the dextran molecules (like hydrogen bonds), whereas they are sterically hindered if larger dextran molecules are used. When the protein concentration was increased from 10 to 100 microg/ml (in formulas with 8% dextran T1), no influence on the protein activity could be found. With regard to the carbohydrate-binding activity of the protein, it was shown that the optimal content of residual water in the lyophilisate should be about 2%. Above and below this percentage a destabilization of the protein was observed. The often discussed failure of dextran as a stabilizing excipient in the freeze-drying of proteins seems to be a question of the selection of the correct molecular weight.

Complex formation of sericoside with hydrophilic cyclodextrins: improvement of solubility and skin penetration in topical emulsion based formulations.

The main objective of this study was to devise novel methods for improving the solubility of the anti-inflammatory triterpenoid sericoside, the main component of Terminalia sericea extract, thus enabling its incorporation into topical formulations. Sericoside was stabilized by complex formation with hydrophilic derivatives of beta- and gamma-cyclodextrins in a molar ratio of 1.0:1.1. The complex of extract and cyclodextrin was equilibrated in water at 25 degrees C for approximately 24 h. The dehydrated complexes of T. sericea extract and cyclodextrin were characterized by differential scanning calorimetry, thermogravimetry analysis and X-ray diffraction. Complex formation with beta-cyclodextrin as well as gamma-cyclodextrin derivatives was detectable using these three analytical tools; however, only complexes with gamma-cyclodextrin derivatives showed stability upon storage after incorporation into topical o/w or w/o formulations. Furthermore, a T. sericea extract/gamma-cyclodextrin complex incorporated in an o/w formulation resulted in a 2.6-fold higher percutaneous penetration of sericoside in in vitro excised pig skin as compared to pure T. sericea extract. For the first time, the virtually insoluble anti-inflammatory active sericoside was incorporated into a topical emulsion based formulation in a stable manner, resulting in efficient skin penetration.

Cortical activation to auditory mismatch elicited by frequency deviant and complex novel sounds: a PET study.

The analysis of auditory deviant events outside the focus of attention is a fundamental capacity of human information processing and has been studied in experiments on Mismatch Negativity (MMN) and the P3a component in evoked potential research. However, generators contributing to these components are still under discussion. Here we assessed cortical blood flow to auditory stimulation in three conditions. Six healthy subjects were presented with standard tones, frequency deviant tones (MMN condition), and complex novel sounds (Novelty condition), while attention was directed to a nondemanding visual task. Analysis of the MMN condition contrasted with thestandard condition revealed blood flow changes in the left and right superior temporal gyrus, right superior temporal sulcus and left inferior frontal gyrus. Complex novel sounds contrasted with the standard condition activated the left superior temporal gyrus and the left inferior and middle frontal gyrus. A small subcortical activation emerged in the left parahippocampal gyrus and an extended activation was found covering the right superior temporal gyrus. Novel sounds activated the right inferior frontal gyrus when controlling for deviance probability. In contrast to previous studies our results indicate a left hemisphere contribution to a frontotemporal network of auditory deviance processing. Our results provide further evidence for a contribution of the frontal cortex to the processing of auditory deviance outside the focus of directed attention.

Properties of ibuprofen crystallized under various conditions: a comparative study.

Different crystal forms of the analgesic drug ibuprofen were prepared and characterized in this study. Various conditions were used for the crystallization: crystallization was carried out using the solvent change method, the temperature change method, and the solvent evaporation method. Crystals were grown from different solvents. Different crystal forms with different properties were observed: cubic, needle-shaped, and plate-shaped crystals were obtained. Spherical agglomeration occurs when crystallization is carried out in acetonitrile or methanol. Flowability of these spherical crystals is increased. All crystals were determined as isomorphic by differential scanning calorimetry and x-ray analysis--which queries doubtful results of recent publications. Properties like dissolution behavior and properties influencing the manufacturing of dosage forms--like flowability--differ. Thus the choice of the optimal preparation method influencing the crystal habit is important in manufacturing the drug ibuprofen.

Jet milling--a new technique for microparticle preparation.

An innovative technique for solvent free preparation of microparticles is described. Microparticles were prepared by a melt grinding technique which consists of three consecutive steps of melting in case of placebo microparticles or co-melting of polymer and drug in case of drug loaded microparticles, respectively, and pregrinding. In a final jet milling step the reduction of the particle size and smoothening of the microparticle surface occurred. Different polymers of PLA and PLGA type were utilised. The influence of the preparation parameters during the process were investigated according to microparticle properties like particle size distribution, habitus or surface morphology by executing a 2((5-2)) factorial design. The minimum mean particle size distribution (x(50) value) reached 4-6 microm. Scanning electron microscopy revealed that non-porous microparticles with a smooth surface were prepared. The release pattern of estrioltriacetate loaded microparticles of Resomer 202H nearly followed a zero order release kinetic over a period of 21 days without an initial burst effect. The preparation process can be carried out in a reproducible manner. The results demonstrate that microparticle preparation is possible by the following unique melt grinding technique without using organic solvents.

The movement-related potential in children with migraine and tension-type headache.

Migraine is characterized by an elevated contingent negative variation (CNV) in adults and children. In the present study the movement-related potential preceding self-initiated movements, the Bereitschaftspotential, was investigated in 30 children (mean age 12 years) who were suffering from migraine and tension-type headache and in 16 healthy age-matched controls. Children pressed a button 80 times with the right index finger while movement-related potentials were recorded from frontal and central electrodes. Whereas healthy children evidenced positive movement-related potentials at left and midline positions, children with migraine and tension-type headache showed negative movement-related potentials at midline leads without lateralization. Negativity was even more pronounced in cases of migraine with than without aura symptoms.

Formulating and stability of benzodiazepines in a new lipid emulsion formulation.

The objective of the current study was to evaluate the novelty of a new lipid emulsion formulation containing 30% oil phase as a drug delivery system. Therefore different benzodiazepines (BZs), namely diazepam, tetrazepam, clonazepam and lorazepam, were incorporated into this emulsion formulation. This lipid emulsion formulation showed enhanced solubilization capacity as 10 mg/ml, 10 mg/ml, 0.9 mg/ml, and 1.8 mg/ml formulations for diazepam, tetrazepam, clonazepam, and lorazepam were achieved, respectively. Incorporating the drugs into the lipid emulsion did not alter its physicochemical properties. Also the free and the drug emulsion formulations displayed good physical stability after autoclaving and after around one year of storage at shelf, as no changes in the physicochemical properties were observed. Most drugs also showed stable behavior after autoclaving and after approximately 1 year of storage at shelf. The only exception was lorazepam, as only around 50% of the drug was still intact after autoclaving.

Novelty-elicited mismatch negativity in patients with schizophrenia on admission and discharge.

OBJECTIVE: Given recent reports of differences between mismatch negativity (MMN) elicited by always novel sounds (novelty-elicited MMN) and that elicited by repeated rare deviants (conventional MMN), we investigated novelty-elicited MMN and P3a in patients with schizophrenia before and after a nonstandardized inpatient treatment. DESIGN: Electrophysiological and clinical assessment of patients on admission and discharge from hospital. Assessment of control subjects on 2 sessions. SETTING: Inpatient treatment in a psychiatric university hospital. SUBJECTS: 20 patients with schizophrenia and 21 healthy control subjects of similar age and sex. Selection of patients with first- to third-episode schizophrenia. OUTCOME MEASURES: Early and late component MMN amplitudes and latencies, P3a amplitudes and latencies, Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), Extrapyramidal Symptom Scale (EPS), Abnormal Involuntary Movement Scale (AIMS) and chlorpromazine equivalents. RESULTS: In patients with schizophrenia, novelty-elicited MMN was unimpaired on admission, and there was a statistically significant reduction of the late MMN component with treatment. Improvements in symptom expression were associated with increased latencies of the early MMN component. CONCLUSION: Results indicate differences in information processing between conventional and novelty-elicited MMN. Some components of the novelty-elicited MMN might be more state dependent than those of the conventional MMN.

Development of a novel parenteral formulation for tetrazepam using a lipid emulsion.

A novel parenteral formulation for tetrazepam (10 mg/ml) was developed using lipid emulsions. This formulation utilized a new lipid emulsion formulation, which was developed by changing the polarity of the oil phase. It was found that increasing the polarity of the oil phase resulted in enhanced solubility of tetrazepam. Tetrazepam showed higher solubility in a mixture of castor oil and middle-chain triglycerides (MCTs) (1:1) than in any other oil investigated. This mixture resulted in low interfacial tension and moderate viscosity, which seemed to be the optimum oil phase. In addition, to increase the concentration of tetrazepam, an emulsion formulation containing 30% oil phase was produced and optimized. The drug-free emulsion formulation showed fine particle sizes with an imperceptible change in physicochemical properties after more than 2 years on the shelf. As a result, it was possible to produce a parenteral emulsion formulation containing 10 mg/ml tetrazepam. No change in the physicochemical properties of the emulsion was observed after the addition of tetrazepam. The tetrazepam emulsion showed stable behavior during the autoclaving process and good shelf stability for at least 10 months as well. Tetrazepam itself also displayed good stability during the autoclaving process and also showed good shelf stability in this emulsion formulation.

Neuropsychological and conditioned blocking performance in patients with schizophrenia: assessment of the contribution of neuroleptic dose, serum levels and dopamine D2-receptor occupancy.

Patients with schizophrenia show impairments of attention and neuropsychological performance, but the extent to which this is attributable to antipsychotic medication remains largely unexplored. We describe here the putative influence of the dose of antipsychotic medication (chlorpromazine equivalents, CPZ), the antipsychotic serum concentration of dopamine (DA) D2-blocking activity and the approximated central dopamine D2-receptor occupancy (DA D2-occupancy), on conditioned blocking (CB) measures of attention and performance on a neuropsychological battery, in 108 patients with schizophrenia (compared with 62 healthy controls). Antipsychotic serum concentration and D2-occupancy were higher in patients with a paranoid versus non-paranoid diagnosis, and in female versus male patients (independent of symptom severity). Controlling for D2-occupancy removed the difference between high CB in paranoid and impaired low CB in non-paranoid patients. Similar partial correlations for antipsychotic drug dose and serum levels of DA D2-blocking activity with performance of the trail-making and picture completion tests (negative) and the block-design task (positive) showed the functional importance of DA-related activity. High estimates of central DA D2-occupancy were related to impaired verbal fluency but were associated with improved recall of stories, especially in paranoid patients. This, the first study of its kind, tentatively imputes a role for DA D2-related activity in left frontal (e.g. CB, verbal fluency) and temporal lobe functions (verbal recall) as well as in some non-verbal abilities mediated more in the right hemisphere in patients with schizophrenia.

Characterization of co-polymers of lactic and glycolic acid for supercritical fluid processing.

Polymers of lactic and glycolic acid are often used for the production of injectible microparticles with controlled drug release. In the variety of processes used for the microparticle formulation, the Aerosol Solvent Extraction System (ASES) is rather special. Microparticle formation and drying take place in one step by precipitating a methylene chloride solution of the polymer in supercritical CO2. This process sets special requirements to the polymers in crystallinity, solubility, and thermal behavior that are best fulfilled by blocked copolymers. This study investigates a number of lactide-co-glycolide polymers with blocked distribution of the co-monomers by NMR spectroscopy and powder diffraction. The molar ratios are determined by 1H-NMR spectroscopy to verify the manufacturer's declarations of the purchased specimens. Additionally, the block length is determined by application of 13C-NMR. Therefore, a method reported in the literature was modified and evaluated in order to calculate the length of lactide and glycolide sequences in the polymer. Furthermore, this study looks at the impact of synthesis conditions on block length and crystallinity, and the impact of the blocking on both, crystallinity and solubility of the polymers.

The influence of alkali fatty acids on the properties and the stability of parenteral O/W emulsions modified with solutol HS 15.

Arachis oil based parenteral O/W emulsions were prepared using soya bean phosphatidylcholine (SPC) and different combinations of co-emulsifiers containing polyethylene glycol fatty acid esters (Solutol HS 15) and alkali fatty acids (sodium laurate, sodium stearate). The parameters measured were droplet size (both by photon correlation spectroscopy and laser diffractometry), pH and zeta potential. All emulsions were subjected to autoclaving. The addition of polyethylene glycol 12-hydroxy stearate (Solutol HS 15) led to a significant decrease of mean oil droplet size. For long-term stability the amount added turned out to be the most important factor. With increased amounts of Solutol HS 15 the packing density of the emulsifier layer and the zeta potential decreased leading to instability. The optimum load of Solutol HS 15 was found to be 15 micromol/ml. Alkali fatty acids markedly improved the physical stability of the emulsions. Improved stability properties conferred to emulsions by alkali fatty acids could be attributed to the zeta potential increase even in the presence of Solutol HS 15. Consequently a mixed emulsifier film was established in which the ionized fatty acids determined the interface charge. In addition to this a strengthening of the molecular interactions occurring between phospholipid and Solutol HS 15 emulsifier in the presence of ionized fatty acids at the O/W interface can be assumed (L. Rydhag, The importance of the phase behaviour of phospholipids for emulsion stability, Fette Seifen Anstrichm. 81 (1979) 168-173). Different co-emulsifier mixtures were shown to have a pronounced impact on the plasma protein adsorption onto emulsion droplets.