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Biomedical subjects

H Kranz

Publications and source records attributed to H Kranz.

At least 19 recordsLinked to original sources
PubMed2006

A novel in situ forming drug delivery system for controlled parenteral drug delivery.

The objective of this study was to investigate the in vitro drug (diltiazem hydrochloride and buserelin acetate) release from different in situ forming biodegradable drug delivery systems, namely polymer solutions (in situ implants) and in situ microparticle (ISM) systems. The drug release from ISM systems [poly(d,l-lactide) (PLA) or poly(d,l-lactide-co-glycolide) (PLGA)-solution dispersed into an external oil phase] was investigated as a function of the type of solvent and polymer, polymer concentration and internal polymer phase:external oil phase ratio and was compared to the drug release from in situ implant systems and microparticles prepared by conventional methods (solvent evaporation or film grinding). Upon contact with the release medium, the internal polymer phase of the ISM system solidified and formed microparticles. The initial drug release from ISM systems decreased with increasing polymer concentration and decreasing polymer phase:external oil phase ratio. The type of biocompatible solvent also affected the drug release. It decreased in the rank order DMSO>NMP>2-pyrrolidone. In contrast to the release of the low molecular weight diltiazem hydrochloride, the peptide release (buserelin acetate) was strongly dependent on the polymer degradation/erosion. One advantage of the ISM system when compared to in situ implant systems was the significantly reduced burst effect because of the presence of an external oil phase. ISM systems resulted in drug release profiles comparable to the drug release of microparticles prepared by the solvent evaporation method. Therefore, the ISM systems are an attractive alternative to existing complicated microencapsulation methods.

Buserelin↗
PubMed2005

Effects of formulation and process variables on the release of a weakly basic drug from single unit extended release formulations.

A new commercially available extended release matrix material, Kollidon SR, composed of polyvinylacetate (PVA) and polyvinylpyrrolidone (PVP), was evaluated with respect to its ability to modulate the in vitro release of the weakly basic drug ZK 811 752. The effect of different formulation and process parameters on the release kinetics of ZK 811 752 from PVA/PVP based matrix tablets was investigated as a function of the (i) nature of excipient added to the drug-polymer mixtures, (ii) method of manufacturing (direct compression versus wet granulation), and (iii) effect of a post-compression curing step. ZK 811 752 containing extended release matrix tablets were successfully prepared by using Kollidon SR. The drug release from the matrix tablets increased by the addition of excipients such as maize starch, lactose and calcium phosphate. Addition of the highly swellable maize starch and the water-soluble lactose accelerated the drug release in a more pronounced manner compared to the water-insoluble calcium phosphate. Compound release from matrix tablets prepared by wet granulation was faster compared to the drug release from tablets prepared by direct compression. Post compression curing did not influence the drug release rate from drug-lactose-Kollidon SR formulations. Stability studies demonstrated no degradation of the drug substance and reproducible drug release patterns for matrix tablets stored at 25 degrees C/60% RH and 30 degrees C/70% RH for up to 6 months.

Calcium Phosphates↗
PubMed2005

Development of a multi particulate extended release formulation for ZK 811 752, a weakly basic drug.

ZK 811 752, a potent candidate for the treatment of autoimmune diseases, demonstrated pH-dependent solubility. The resulting release from conventional mini matrix tablets decreased with increasing pH-values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Mini matrix tablets were prepared by direct compression of drug, matrix former (polyvinylacetate/polyvinylpyrrolidone; Kollidon SR) and excipients (lactose, calcium phosphate or maize starch). To solve the problem of pH-dependent solubility fumaric acid was added to the drug-polymer excipient system. The addition of fumaric acid was found to maintain low pH-values within the mini tablets during release of ZK 811 752 in phosphate buffer pH 6.8. Thus, micro environmental conditions for the dissolution of the weakly basic drug were kept constant and drug release was demonstrated to be pH-independent. Incorporation of water-soluble (lactose) or highly swellable (maize starch) excipients accelerated drug release in a more pronounced manner compared to the water-insoluble excipient calcium phosphate. Stability studies demonstrated no degradation of the drug substance and reproducible drug release patterns for mini matrix tablets stored at 25 degrees C/60% RH and 30 degrees C/70% RH for up to 6 months.

Calcium Phosphates↗
PubMed2005

Development of a single unit extended release formulation for ZK 811 752, a weakly basic drug.

ZK 811 752, a potent candidate for the treatment of autoimmune diseases, demonstrated pH-dependent solubility. The resulting release from conventional matrix tablets decreased with increasing pH-values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Three different polymers were used as matrix formers, the partly water-soluble and poorly swellable mixture of polyvinylacetate/polyvinylpyrrolidone, the water-insoluble and almost unswellable ethylcellulose (EC) and the water-soluble and highly swellable hydroxypropyl methylcellulose (HPMC). To solve the problem of pH-dependent solubility different organic acids, such as fumaric, tartaric, adipic, glutaric and sorbic acid were added to the drug-polymer system. The addition of organic acids to all three matrix formers was found to maintain low pH-values within the tablets during release of ZK 811 752 in phosphate buffer pH 6.8. Thus, the micro-environmental conditions for the dissolution of the weakly basic drug were kept almost constant. An extended release matrix tablet for ZK 811 752 consisting of drug, polymer and organic acid providing the desired pH-independent drug release has been developed.

Chemistry, Pharmaceutical↗
PubMed2001

Myotoxicity studies of injectable biodegradable in-situ forming drug delivery systems.

The objective of the study was to investigate the potential in-vitro and in-vivo myotoxicity of different in-situ forming biodegradable drug delivery systems, namely in-situ Microparticle (ISM) systems and polymer solutions (in-situ implant systems). The acute myotoxicity was evaluated in-vitro using the isolated rodent skeletal muscle model by measuring the cumulative creatine kinase (CK) efflux. For the in-vivo study, following intramuscular injection (i.m.) into male Sprague Dawley rats, the area under the plasma CK-curve was used to evaluate muscle damage. The formulations included ISM-systems [a poly (lactide)-solvent phase dispersed into an external oil phase] and poly (lactide) solutions (in-situ implant systems). Phenytoin and normal saline served as positive and negative controls, respectively. Poly (lactide) in different solvents (in-situ implant systems) resulted in 14.4-24.3 times higher CK-values compared to normal saline, indicating a high myotoxic potential. With the ISM-system, the CK-release was significantly lower, decreased with a lower polymer phase: oil phase ratio, and approached the values of normal saline at a ratio of 1:4. Bupivacaine HCl- and Buserelin acetate- containing ISM-systems resulted in significantly lower CK-levels when compared to the corresponding drug formulation in normal saline. The in-vivo studies confirmed the in-vitro data and showed good muscle compatibility of the ISM-systems.

Animals↗
PubMed2000

Sequence and analysis of chromosome 3 of the plant Arabidopsis thaliana.

Arabidopsis thaliana is an important model system for plant biologists. In 1996 an international collaboration (the Arabidopsis Genome Initiative) was formed to sequence the whole genome of Arabidopsis and in 1999 the sequence of the first two chromosomes was reported. The sequence of the last three chromosomes and an analysis of the whole genome are reported in this issue. Here we present the sequence of chromosome 3, organized into four sequence segments (contigs). The two largest (13.5 and 9.2 Mb) correspond to the top (long) and the bottom (short) arms of chromosome 3, and the two small contigs are located in the genetically defined centromere. This chromosome encodes 5,220 of the roughly 25,500 predicted protein-coding genes in the genome. About 20% of the predicted proteins have significant homology to proteins in eukaryotic genomes for which the complete sequence is available, pointing to important conserved cellular functions among eukaryotes.

Arabidopsis↗
PubMed2000

Calculation of the required size and shape of hydroxypropyl methylcellulose matrices to achieve desired drug release profiles.

The aim of this study was to develop methods for the design of hydroxypropyl methylcellulose (HPMC) tablets with specified drug profiles. This was achieved by the use of a mathematical model developed to predict the release kinetics of water-soluble drugs from HPMC matrices. The required model parameters were determined experimentally for propranolol HCl and chlorpheniramine maleate in 0. 1 N HCl and phosphate buffer pH 7.4, respectively. Then, the effects of the dimensions and aspect ratio (radius/height) of the tablets on the drug release rate were evaluated. Independent experiments were conducted to verify the theoretical predictions. Acceptable agreement between theory and experiment was found, irrespective of the type of release medium and drug. However, statistical analysis revealed a structure in the resulting residuals. Drug release rates are overestimated at the beginning and underestimated at the end of the process. Possible explanations and modifications of the model are thoroughly discussed. Both, theoretical and experimental data showed that a broad spectrum of drug release patterns can be achieved by varying the size and shape of the tablet. The effect of the initial matrix radius on release was found to be more pronounced than the effect of the initial thickness. The practical benefit of the proposed method is to predict the required size and shape of new controlled drug delivery systems to achieve desired release profiles, thus significantly facilitating the development of new pharmaceutical products.

Algorithms↗
PubMed2000

Physicomechanical properties of biodegradable poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) films in the dry and wet states.

The objective of this study was to investigate the mechanical properties (% elongation and puncture strength) of poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) films as a function of exposure time to an aqueous medium and to correlate the mechanical properties to the degradation/erosion of the polymer as a function of the type of polymer [PLA, weight-average molecular weight (M(W)) 270,300, or PLGA 50:50, M(W) 56,500], the type of plasticizer [(triethyl citrate (TEC) or acetyltributyl citrate (ATBC)], and the exposure time to pH 7.4 phosphate buffer. The glass transition temperature of the films was measured by differential scanning calorimetry (DSC), the molecular weight by size exclusion chromatography (SEC), and the polymer erosion and hydration gravimetrically. The mechanical properties were strongly affected by the type of polymer and plasticizer. PLGA films showed a faster loss of mechanical integrity. TEC, the water-soluble plasticizer, leached from the films, resulting in major differences in the mechanical properties (flexibility) when compared with films plasticized with the more permanent, water-insoluble ATBC. A significant difference in M(W) decrease was seen between plasticizer-free and plasticizer-containing PLA films, but not for PLGA films. Plasticized PLA films, which were above their glass transition temperature in the rubbery state, showed a faster decrease in M(W) than plasticizer-free PLA ones, which were in the glassy state. The plasticizer addition to the lower M(W) PLGA did not enhance the polymer degradation; the plasticizer-free PLGA was already in the rubbery state. Major differences between the two polymers were also seen in the mass loss and the water uptake studies. After 4 weeks, the mass loss was between 2.6 and 7.0% and the water uptake between 10.1 and 21.1% for PLA films, whereas for PLGA films, the mass loss was between 40.3 and 51.3% and the water uptake between 221.9 and 350.6%. 2000 Wiley-Liss, Inc.

Biocompatible Materials↗
PubMed2000

c-MYB oncogene-like genes encoding three MYB repeats occur in all major plant lineages.

Since the identification of the first plant MYB-like protein, the Zea mays factor C1, the number of MYB-related genes described has greatly increased. All of the more than 150 plant MYB-like proteins known so far contain either two or only one sequence-related helix-turn-helix motif in their DNA-binding domain. Animal c-MYB genes contain three such helix-turn-helix motif-encoding repeats (R1R2R3 class genes). It has therefore been concluded that R2R3-MYB genes are the plant equivalents of c-MYB and that there are significant differences in the basic structure of MYB genes of plants and animals. Here, we describe expressed R1R2R3-MYB genes from Physcomitrella patients++ and Arabidopsis thaliana, designated PpMYB3R-1 and AtMYB3R-1. The amino acid sequences of their DNA-binding domains show high similarity to those of animal MYB factors, and less similarity to R2R3-MYB proteins from plants. In addition, R1R2R3-MYB genes were identified in different plant evolutionary lineages including mosses, ferns and monocots. Our data show that a DNA-binding domain consisting of three MYB repeats existed before the divergence of the animal and plant lineages. R1R2R3-MYB genes may have a conserved function in eukaryotes, and R2R3-MYB genes may predominantly regulate plant-specific processes which evolved during plant speciation.

Amino Acid Sequence↗
PubMed1999

HPMC-matrices for controlled drug delivery: a new model combining diffusion, swelling, and dissolution mechanisms and predicting the release kinetics.

PURPOSE: The purpose of this study was to investigate the drug release mechanisms from hydroxypropyl methylcellulose (HPMC)-matrices, and to develop a new model for quantitative predictions of controlled drug delivery. METHODS: The dissolved mass of pure HPMC-matrices and the drug release rate from propranolol HCl-loaded HPMC-matrices were determined experimentally. Based on Fick's second law of diffusion for cylinders, the transport of water and drug were modeled considering (i) both radial and axial diffusion, (ii) concentration-dependent drug diffusivities, (iii) matrix swelling and (iv) HPMC dissolution. RESULTS: Good agreement between theory and experiment (dissolved mass and drug release studies) was obtained, proving the validity of the presented model. The water and drug diffusivities are strongly dependent on the matrix swelling ratio. Diffusion, swelling and dissolution are the governing mechanisms involved in the overall drug release process. CONCLUSIONS: The practical benefit of the presented model is to identify the required shape and dimensions of drug-loaded HPMC-matrices in order to achieve desired release profiles, thus facilitating the development of new controlled drug delivery products. This will be demonstrated in a future study.

Delayed-Action Preparations↗
PubMed1994

The tripartite DNA element responsible for diet-induced rat fatty acid synthase (FAS) regulation.

We investigated which region of the 5'-flanking sequence of the rat fatty acid synthase (FAS)-encoding gene could be responsible for its nutritionally regulated expression. Diet-induced differences in chromatin structure were determined by DNase I treatment of intact nuclei from hepatic tissue. A low-fat diet results in a different pattern of DNase I-hypersensitive sites (HS) in the chromatin of the FAS promoter (pFAS) from that seen when the nuclear extract was prepared from the livers of normally fed rats. The protein-binding properties of the region defined by DNase I hypersensitivity were tested by gel retardation. A putative cis-acting element with a tripartite structure, 5'-GCCT, 6-bp spacer and a 3'-palindrome, could be localized between bp -518 to -495 in pFAS. Competition experiments with oligodeoxyribonucleotides (oligos) representing subfragments of this cis-element showed that the requirement for structure is stricter than that for sequence. This element could be one of the termini of the insulin-induced signal cascade.

Animals↗
PubMed1985

Relation between electromyogram and force in fatigue.

The relationship between the surface electromyogram (SEMG) and force was examined during maximal voluntary contraction (MVC). Isometric MVC of elbow flexors were studied in 18 subjects who performed 27 trials, each consisting of six MVCs lasting 45 s at intervals of 30 s. There was a decrease in the median frequency (Fm) of the SEMG and of the compound action potentials (CAP) during MVC. The CAPs demonstrated that the fall in Fm was associated with a proportional increase in signal power, whereas CAP amplitude did not decrease, indicating intact neuromuscular transmission. The SEMG root-mean-square amplitude remained fairly constant, progressively deviating from force with time of contraction (r = 0.40). When SEMG amplitude was corrected for the Fm change, it tracked force more closely (r = 0.68), indicating a fall in motoneuron drive during MVC. The corrected SEMG was used to calculate the change in the generalized firing rate of motoneurons. The firing rate decreased 60% in the first and sixth contractions, tracked force closely, and corresponded to the firing rate fall seen in late adaptation of motoneurons (r = 0.90, P less than 0.001).

Action Potentials↗
PubMed1984

Muscle spasms associated with Sudeck's atrophy after injury.

Four patients developed abnormal involuntary movements of a limb after injury. All subsequently developed sympathetic algodystrophy with Sudeck's atrophy and then abnormal muscle spasms or jerks of the affected limb, lasting years. Sympathetic block in three patients did not relieve the abnormal movements. Two patients obtained partial recovery spontaneously, but the other two required surgery for relief. The pathophysiology of this condition remains to be determined but the evidence suggests that it is a distinct, disabling clinical syndrome.

Adult↗
PubMed1983

Acupuncture treatment of chronic back pain. A double-blind placebo-controlled trial.

Acupuncture treatment of chronic low back pain was studied in a placebo-controlled double-blind crossover trial completed by 77 patients. The patients had significantly increased depression, neuroticism, and hypochondriasis scores. Initial pain levels correlated with state-anxiety, depression, pain duration, and abnormal illness behavior measures, as well as with the intake of psychotropic but not analgesic medication. Overall reduction in pain score was 26 percent for acupuncture and 22 percent for placebo treatment; the difference was not significant (p greater than 0.6). Analgesic drug intake was reduced to a similar extent in both groups. During the first phase of treatment, patients receiving acupuncture had a greater but not significantly different reduction in pain rating scores compared with those receiving placebo (t = 0.52; p greater than 0.6). This group showed significantly lower pain scores (p less than 0.05) in the second phase of the trial while receiving placebo treatment. Overall reduction in individual patient's pain score was best predicted by initial pain severity (r = 0.43; p less than 0.001) and psychotropic drug intake (r = 0.37; p less than 0.001). None of the variables tested predicted which patients would specifically respond to acupuncture or placebo.

Acupuncture Therapy↗
PubMed1983

Factors determining the frequency content of the electromyogram.

The contribution of central and peripheral factors to the frequency content of the electromyogram was examined in 10 subjects performing maximal 45-s contractions of thenar muscles. The median frequencies (Fm) of surface-recorded electromyograms and compound action potentials were similar early (P greater than 0.6) and late (P greater than 0.5) in the contractions. There was a mean decrease in the Fm during contraction of 39% for electromyograms and 35% for compound potentials (P greater than 0.1). The Fm of electromyograms increased 11% (P less than 0.02) in only the 1st s of contraction as force was raised from 25 to 100% of maximum. Only one of five subjects showed evidence of increasing synchronization of motor unit discharge during contraction. There was no evidence that delay or dispersion of action potential propagation in terminal nerve fibers or at the neuromuscular junction had a significant effect on frequency content. The findings indicated that the spectral content of muscle electrical activity, and its shift during contraction, primarily reflects intrinsic muscle properties.

Adult↗