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Biomedical subjects

B Bittner

Publications and source records attributed to B Bittner.

17 recordsLinked to original sources
PubMed2003

Pre-emptive treatment of CMV DNAemia in paediatric stem cell transplantation: the impact of recipient and donor CMV serostatus on the incidence of CMV disease and CMV-related mortality.

Cytomegalovirus (CMV) DNAemia was detected by PCR in 30/125 (24%) consecutive paediatric patients undergoing allogeneic stem cell transplantation. All patients with CMV DNAemia received pre-emptive ganciclovir until two consecutive negative results were obtained. CMV-IgG-positive patients (R+) had a significantly increased risk of DNAemia as compared to CMV-IgG-negative (R-) patients (62% vs 8%) P<0.0001. The incidence of DNAemia was 71% (10/14) in R+ transplanted from seronegative donors (D-) compared to 54% (13/32) in those transplanted from seropositive donors (D+). Of 30 (40%) children with DNAemia, 12 developed CMV disease despite pre-emptive treatment. The overall incidence of disease was 0% (0/59) for R-/D-, 9% (3/23) for R+/D+, 7% (2/29) for R-/D+ and 57% (8/14) for R+/D-. In patients with DNAemia, 4/20 (20%) patients with D+ and 8/10 (80%) with D- became symptomatic. In the multivariate analysis of both groups, patients at risk (R+ and/or D+) and patients with DNAemia, a negative donor serostatus was the only factor associated with a significantly increased incidence of disease. Seven of 9 patients with lethal CMV disease had received CMV-IgG-negative grafts. The data suggest that in CMV seropositive recipients donor CMV seropositivity is associated with a reduced incidence of CMV disease and a favourable outcome following pre-emptive treatment.

Adolescent↗
PubMed2001

The use of election paramagnetic resonance spectroscopy in early preformulation experiments: the impact of different experimental formulations on the release of a lipophilic spin probe into gastric juice.

The lipophilic spin probe TEMPOL-benzoate was dissolved in different experimental formulations, including polyethylene glycol 400 (PEG 400), Miglyol, glycerol monooleate (GMO), and Cremophor RH-40. Samples were measured by electron paramagnetic resonance (EPR) spectroscopy before and after addition to human gastric juice. The distance between the first and the third peak in the EPR spectrum (2a(N)) was measured to monitor the polarity of the spin probe's microenvironment. Moreover, the ratio between the signal amplitudes of the second and the third peak (a/b ratio) was used to monitor the mobility of the spin probe in a certain formulation. Thus, by calculating 2a(N) and the a/b ratio of the EPR spectra it was possible to determine a potential release of the spin probe from different formulations into gastric juice. It was found that oily and surface-active vehicles (Miglyol, Cremophor RH-40, and GMO) were more suitable to protect a lipophilic compound from being released within a gastric environment than PEG 400. Our results demonstrate that EPR spectroscopy seems to be a promising tool in early preformulation experiments to monitor the release of spin probes from formulations of different nature. This kind of experiment can be of value for the optimization of exploratory formulations.

Chemistry, Pharmaceutical↗
PubMed2000

Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450.

The use of common formulation ingredients (categorized into six groups) for preclinical animal studies has been assessed with respect to cytochrome P450 (CYP) inhibition, specifically CYP3A inhibition, in expressed human CYP3A4, human liver microsomes, dog- and cynomolgus monkey intestinal microsomes. Results indicated a wide range of inhibition potentials and there appeared to be species differences with inhibition of CYP3A activity. Generally, greater inhibition of CYP3A activity was observed with amphiphilic ingredients (for example mixed micellar solutions, Tween 80, and oleic acid). From the data presented, it can be predicted that the majority of the ingredients tested would not have a significant impact on the potential inhibition, by the formulation, on any apparent first pass metabolism in the intestinal tract for new drug entities being tested in the preclinical environment. However a number of common ingredients will require further investigation based on the estimated concentration within the gastrointestinal tract.

Animals↗
PubMed2000

The impact of co-solvents and the composition of experimental formulations on the pump rate of the ALZET osmotic pump.

The water-miscible co-solvents polyethylene glycol 400 (PEG400), N-methyl-2-pyrrolidone (NMP), and N, N-dimethylacetamide (DMA) exhibit the potential to increase the solubility of poorly water-soluble compounds and therefore they represent promising vehicles for compound delivery using osmotic pumps in early discovery experiments. Thus, the selected co-solvents were investigated for their compatibility with the interior of ALZET osmotic pumps. Moreover, 1-week pumps were filled with mixtures of either the co-solvents with water (60:40, v/v), with neat PEG400, or with PEG400/water mixtures of different concentrations. It was determined whether the composition of an experimental formulation could have an impact on the overall pump rate with 14C-mannitol being used as the model compound. It was found that neat PEG400 was compatible with the reservoir material, whereas NMP and DMA were tolerable only in aqueous solutions up to 60%. PEG400, NMP, and DMA mixtures with water (60:40) resulted in release rates comparable to those of water and PEG400/water mixtures of lower co-solvent concentration. Moreover, as demonstrated using the various PEG400/water mixtures, the amount of co-solvent in the formulation had no significant impact on the overall release profile. By contrast, the use of neat PEG400 resulted in a significant decrease in the pump rate.

Drug Delivery Systems↗
PubMed2000

Immunological transitions in response to antigenic mutation during viral infection.

Antigenic variation is an important factor in viral persistence and disease progression. We analyze immunological changes which occur in response to antigenic mutation during chronic viral infection. Using an established model of viral and immune system dynamics, we determine which qualitative shifts in the immune response can be elicited by the appearance of a new mutant. We find that antigenic mutation can cause dramatic shifts in the magnitude and type of anti-viral immune response. For example, the appearance of a mutant can elicit a new immune response which recognizes the original viral strain. We also find that novel strains of the virus which replicate more slowly than existing viral strains are able to invade and survive, even when the immune system is capable of mounting an immune response against the mutant.

Animals↗
PubMed1999

Degradation and protein release properties of microspheres prepared from biodegradable poly(lactide-co-glycolide) and ABA triblock copolymers: influence of buffer media on polymer erosion and bovine serum albumin release.

The aim of the present study was to investigate the influence of the chemical insertion of poly(ethylene oxide), PEO, into a poly(lactide-co-glycolide), PLG, backbone on the mechanisms of in vitro degradation and erosion of the polymer. For this purpose microspheres prepared by a modified W/O/W double emulsion technique using ABA triblock copolymers, consisting of PLG A-blocks attached to central PEO B-blocks were compared with microspheres prepared from PLG. Due to their molecular architecture the ABA triblock copolymers differed in their erosion and degradation behavior from PLG. Degradation occurred faster in the ABA polymers by cleavage of ester bonds inside the polymer backbone. Even erosion was shown to start immediately after incubation in different buffer media. By varying pH and ionic strength of the buffer it was found that both mass loss and molecular weight decay were accelerated in alkaline and acidic pH in the case of the ABA triblock copolymers. Although the pH of the medium had a moderate influence on the degradation of PLG, the molecular weight decay was not accompanied by a mass loss during the observation time. In a second set of experiments we prepared bovine serum albumin, BSA, loaded microspheres from both polymers. The release of BSA from ABA microspheres under in vitro conditions parallels the faster swelling and erosion rates. This could be confirmed by electron paramagnetic resonance, EPR, measurements with spin labeled albumin where an influx of buffer medium into the ABA microspheres was already observed within a few minutes. In contrast, PLG microspheres revealed a burst release without any erosion. The current study shows that the environmental conditions affected the degradation and erosion of the pure polymer microspheres in the same way as the release of the model protein. This leads to the conclusion that the more favorable degradation profile of the ABA triblock copolymers was responsible for the improvement of the release profile.

Animals↗
PubMed1999

Biodegradable recombinant human erythropoietin loaded microspheres prepared from linear and star-branched block copolymers: influence of encapsulation technique and polymer composition on particle characteristics.

Recombinant human erythropoietin (EPO) and fluorescein isothiocyanate labeled dextran (FITC-dextran) loaded microspheres were prepared by a modified W/O/W double-emulsion technique. Biodegradable linear ABA block copolymers consisting of poly(L-lactide-co-glycolide) A blocks attached to central poly(ethyleneoxide) (PEO) B blocks and star-branched AB block copolymers containing A blocks of poly(L-lactide) or poly(L-lactide-co-glycolide) and star-branched poly(ethyleneoxide) B blocks were investigated for their potential as sustained release drug delivery systems. Microsphere characteristics were strongly influenced by the polymer composition. In the case of the linear block copolymers, a reduced lactic acid content in a linear block copolymer yielded smaller particles, a lower encapsulation efficiency, and a higher initial drug release both in the case of EPO and FITC-dextran. The investigation of the effects of several manufacturing parameters on microsphere formation showed that the process temperature plays an important role. Microsphere formation in a +1 degrees C environment resulted in higher drug loadings without increasing the amount of residual dichloromethane inside the particles. Other parameters such as the homogenization of the primary W/O emulsion and of the W/O/W double-emulsion have less impact on microsphere characteristics. Branched block copolymers containing star-shaped PEO also showed potential for the preparation of drug loaded microspheres. A certain amount of glycolic acid in the copolymer was necessary for the successful preparation of non-aggregating microspheres at room temperature. Again, the processing temperature strongly affected particle characteristics. Microsphere preparation at +1 degrees C allows the formation of microspheres from a polymer not containing glycolic acid, a result which could not be achieved at room temperature. Moreover, compared to microsphere formation at room temperature, the effective FITC-dextran loading was increased. Concerning the EPO loaded microspheres, the amount of EPO aggregated was comparable to that using the linear ABA polymers. A continuous release of the protein from these star-shaped polymers could not be achieved. In conclusion, apart from microsphere preparation in a +1 degrees C environment the choice of the polymer represents the main factor for a successful entrapment of proteins into biodegradable microspheres.

Biodegradation, Environmental↗
PubMed1999

Tetracycline-HCl-loaded poly(DL-lactide-co-glycolide) microspheres prepared by a spray drying technique: influence of gamma-irradiation on radical formation and polymer degradation.

Tetracycline-HCl (TCH)-loaded microspheres were prepared from poly(lactide-co-glycolide) (PLGA) by spray drying. The drug was incorporated in the polymer matrix either in solid state or as w/o emulsion. The spin probe 4-hydroxy-2,2,6, 6-tetramethyl-piperidine-1-oxyl (TEMPOL) and the spin trap tert-butyl-phenyl-nitrone (PBN) were co-encapsulated into the TCH-loaded and placebo particles. We investigated the effects of gamma-irradiation on the formation of free radicals in polymer and drug and the mechanism of chain scission after sterilization. Gamma-Irradiation was performed at 26.9 and 54.9 kGy using a 60Co source. The microspheres were characterized especially with respect to the formation of radicals and in vitro polymer degradation. Electron paramagnetic resonance (EPR) spectroscopy, gel permeation chromatography (GPC), differential scanning calorimetry (DSC), high-performance liquid chromatography (HPLC), gas chromatography-mass spectroscopy (GC-MS), and scanning electron microscopy (SEM) were used for characterization of the microspheres. Using EPR spectroscopy, we successfully detected gamma-irradiation induced free radicals within the TCH-loaded microspheres, while unloaded PLGA did not contain radicals under the same conditions. The relatively low glass transition temperature of the poly(dl-lactide-co-glycolide) (37-39 degrees C) seems to favor subsequent reactions of free radicals due to the high mobility of the polymeric chains. Because of the high melting point of TCH (214 degrees C), the radicals can only be stabilized in drug loaded microspheres. In order to determine the mechanism of polymer degradation after exposure to gamma-rays, the spin trap PBN and the spin probe TEMPOL were encapsulated in the microspheres. gamma-Irradiation of microspheres containing PBN resulted in the formation of a lipophilic spin adduct, indicating that a polymeric radical was generated by random chain scission. Polymer degradation by an unzipping mechanism would have produced hydrophilic spin adducts of PBN and monomeric radicals of lactic or glycolic acid. These degradation products were not detected by EPR. This result is confirmed by the observation that possible diamagnetic reaction products of low molecular weight, consisting of TEMPOL and lactide or glycolide monomers, could not be detected by GC-MS. While an irradiation dose-dependent decrease in molecular weight of PLGA could be verified in agreement with the literature, TCH content of the microspheres was not affected by the exposure to gamma-rays. It can be concluded that EPR spectroscopy in combination with GPC, DSC, and HPLC allows a detailed characterization of the impact of gamma-sterilization on biodegradable parenteral drug delivery systems.

Anti-Bacterial Agents↗
PubMed1998

Recombinant human erythropoietin (rhEPO) loaded poly(lactide-co-glycolide) microspheres: influence of the encapsulation technique and polymer purity on microsphere characteristics.

Recombinant human erythropoietin (EPO) and fluorescein isothiocyanate-labelled dextran (FITC-dextran) loaded biodegradable microspheres were prepared from poly(lactide-co-glycolide) (PLG) by a modified spray-drying technique. This microencapsulation method was compared with the water-in-oil-in-water (w/o/w) double-emulsion method. As expected, microsphere morphology, particle size and particle size distribution strongly depended on the production process. The spray-drying method was found to have a number of advantages compared to the w/o/w double-emulsion technique. The content of residual dichloromethane (DCM) in the final product was significantly lower in case of the microspheres prepared by spray-drying. Concerning EPO loaded microspheres, spray-drying yielded higher encapsulation efficiencies. Although the microspheres obtained by spray-drying are subjected to intensive mechanical and thermal stress during the preparation, the amount of aggregates of EPO in PLG microspheres were not increased compared to the w/o/w technique. Depending on the manufacturing method, addition of cyclic DL-lactide dimers (referred to as monomers in the following) affected the in vitro release profiles of EPO and FITC-dextran from PLG microspheres. Using differential scanning calorimetry it was shown that these low molecular weight substances only seem to be present inside the microspheres produced by spray-drying. DL-Lactide significantly reduced the initial burst release of both EPO and FITC-dextran. While the following release period of EPO was not affected by the DL-lactide content, a more linear FITC-dextran release pattern could be achieved. It can be concluded that the spray-drying technique provides a number of advantages compared to the w/o/w method. The modulation of protein release using low molecular weight additives is of particular interest for parenteral depot systems.

Calorimetry, Differential Scanning↗
PubMed1998

Monitoring microviscosity and microacidity of the albumin microenvironment inside degrading microparticles from poly(lactide-co-glycolide) (PLG) or ABA-triblock polymers containing hydrophobic poly(lactide-co-glycolide) A blocks and hydrophilic poly(ethyleneoxide) B blocks.

PURPOSE: The purpose of this study was to monitor the microenvironment of an encapsulated model protein during the release from biodegradable microparticles (MP) made from three different polymers, namely poly(lactide-co-glycolide) (PLG) and ABA-triblock polymers containing hydrophobic poly(lactide-co-glycolide) A blocks and hydrophilic poly(ethyleneoxide) B blocks with an A:B ratio of 90:10 (ABA1O) and 70:30 (ABA30). METHODS: MP loaded with spin labeled albumin were prepared by a w/o/w technique. The particles were characterized by light scattering and electron microscopy. In vitro release of albumin was determined by size exclusion chromatography. Light microscopic experiments were conducted to visualize water penetration in the matrix. The protein microenvironment inside the degrading microparticles was characterized noninvasively by 2 GHz EPR spectroscopy. RESULTS: Water penetrated rapidly into all MP in the range of few minutes. A burst release was observed for PLG. The release from ABA block-polymers continued for over 14 days despite the rapid solubilization of the protein inside the microparticles. The initial microviscosity of the protein environment inside the ABA particles after exposure to buffer was 2 mm2/s and increased with time. A gradual decrease of the pH to a value of 3.5 was observed within the MP. CONCLUSIONS: The data indicate that the microviscosity and microacidity inside protein loaded microparticles can be studied nondestructively by EPR spectroscopy. Our results clearly demonstrate that ABA-block polymers are superior to PLG allowing a controlled release of proteins from swollen microspheres.

Albumins↗
PubMed1997

Virus load and antigenic diversity.

In this paper, we analyse mathematical models for the interaction between virus replication and immune responses. We show that the immune system can provide selection pressure for or against viral diversity. The paper provides new insights into the relationship between virus load (=the abundance of virus in an infected individual) and antigenic diversity. Antigenic variation can increase virus load during infections, but the correlation between load and diversity in comparisons among different infected individuals can be positive or negative, depending on whether individuals differ in their cross-reactive or strain-specific immune responses. We derive two models: our first model applies to any replicating parasite that can escape from immune responses; our second model includes immune function impairment, and specifically describes infections with the human immunodeficiency virus (HIV).

Antigenic Variation↗
PubMed1989

[Effects of different tray types on the resulting impression].

In addition to the impression material the type of the used impression tray influences the accurat dimensional transfer of the teeth position to the master cast. In total 80 impressions were taken from models of the upper- and lower jaw by using condensation silicone, hydrocolloid, solid and perforated stock trays and acrylic custom trays. After that the casts were measured. The highest conformity with the original could be achieved with a hydrocolloid stock tray. The custom tray for the upper jaw showed short differences to the original model. By using a custom tray for the lower jaw higher dimensional changes occurred. Besides the different impression material thickness, distorsions of the trays should be discussed.

Dental Impression Materials↗
PubMed1981

[Homeostasis of glucose and gastric resection. The influence of the food passage through the duodenum (author's transl)].

In 45 patients there was performed an oral glucose tolerance test after different types of gastric resection (Billroth I, Billroth II, total gastrectomy with a reconstitution with preservation of the food passage through the duodenum, total gastrectomy with exclusion of the duodenum). Additionally some patients with the same type of resection but with different types of stomach disease were investigated. The following results were achieved: 1. An increasingly reduction of the gastric remnant - 60% resection (B I), 75% resection (B II), total gastrectomy - leads after an oral glucose load to increasingly more rapid rise of blood glucose as well as to increasingly higher peak values of blood glucose concentration. 2. In patients with preserved food passage through the duodenum the oral glucose tolerance is significantly better and the secretory capacity of the beta-cells is significantly higher. 3. In spite of the same type of gastric resection patients with different types of stomach disease have as well as different patterns of oral glucose tolerance curve. Patients with Billroth II - gastric resection because of duodenal ulcer have significant more frequently a late postprandial hypoglycemia (without preceding hyperglycemia) than the patients with Billroth II because of ulcer/neoplasma ventriculi.

Adult↗
PubMedDate not supplied

Piperidine renin inhibitors: from leads to drug candidates.

Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identification of two candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-depleted marmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes. In addition, 14 normalizes albuminuria and kidney tissue damage in these rats when given over a period of 4 weeks. These data suggest that treatment of chronic renal failure patients with a renin inhibitor might result in a significant improvement of the disease status.

Animals↗
PubMedDate not supplied

Ultrasonic atomization for spray drying: a versatile technique for the preparation of protein loaded biodegradable microspheres.

Bovine serum albumin (BDA) loaded microspheres with a spherical shape and smooth surface structure were successfully prepared from poly(lactide-co-glycolide) using an ultrasonic nozzle installed in a Niro laboratory spray dryer. Process and formulation parameters were investigated with respect to their influence on microsphere characteristics, such as particle size, loading capacity, and release properties. Preparation of microspheres in yields of more than 50% was achieved using an ultrasonic atomizer connected to a stream of carrier air. Microsphere characteristics could be modified by changing several technological parameters. An increased polymer concentration of the feed generated larger particles with a significantly reduced initial release of the protein. Moreover, microspheres with a smooth surface structure were obtained from the organic polymer solution with the highest viscosity. Microparticles with a low BSA loading showed a large central cavity surrounded by a thin polymer layer in scanning electron microspheres. A high protein loading led to an enlargement of the shell layer, or even to dense particles without any cavities. A continuous in vitro release pattern of BSA was obtained from the particles with low protein loading. Glass transition temperatures (Tg) of the microspheres before and after lyophilization did not differ from those of the BSA loaded particles prepared by spray drying with a rotary atomizer. Analysis of the polymer by gel permeation chromatography indicated that ultrasonication had no effect on polymer molecular weight. Molecular weight and polydispersity of the pure polymer, placebo microspheres prepared by spray drying, and placebo microspheres prepared using the ultrasonic nozzle were in the same range. In conclusion, ultrasonic atomization represents a versatile and reliable technique for the production of protein loaded biodegradable microspheres without inducing a degradation of the polymer matrix. Particle characteristics can be modified by adjusting formulation parameters and atomization conditions in a simple manner.

Aerosols↗
PubMedDate not supplied

Bovine serum albumin loaded poly(lactide-co-glycolide) microspheres: the influence of polymer purity on particle characteristics.

To study the influence of polymer purity on microsphere characteristics, bovine serum albumin (BSA) loaded biodegradable microspheres were prepared by spray drying using two samples of poly(lactide-co-glycolide), PLG, (50:50, mwt = 35 and 69 kDa). Polymer properties were varied by DL-lactide and glycolide addition or by ultrafiltration. While the effective drug loading was not affected by polymer purity, Tg was decreased with increasing monomer and oligomer content. The removal of these low molecular weight substances by ultrafiltration led to a narrower molecular weight distribution compared to the untreated PLG. Concerning the polymer with the higher molecular weight, microsphere morphology was also strongly affected by polymer composition. In contrast to the non-modified PLG, monomer addition yielded particles with a much smoother surface structure. Moreover, in vitro cytotoxicity of the microspheres prepared from the polymer pretreated by ultrafiltration was significantly reduced, whereas monomer addition caused a dramatic decrease of cells surviving contact with the microsphere extract. The in vivo degradation rate of the ultrafiltered microspheres was decreased and as a result, protein release at later times was slowed down. Furthermore, depending on the effective drug loading level, monomer addition resulted in a decrease in the initial protein burst. It can be concluded that the effect of low molecular weight impurities in a polymer on microsphere characteristics and on cytotoxicity cannot be ignored. Their elimination is possible by ultrafiltration.

Animals↗