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Biomedical subjects

R Langer

Publications and source records attributed to R Langer.

At least 217 records · Page 12Linked to original sources
PubMed1996

Prolonged regional nerve blockade. Injectable biodegradable bupivacaine/polyester microspheres.

BACKGROUND: Biodegradable microspheres are a useful method of drug delivery because they are both injectable and biodegradable, eliminating the need for surgical implantation or removal. Previous work has characterized implantable preparations of local anesthetics in polymer pellets for prolonged regional anesthesia. In this article, the authors characterize injectable suspensions of bupivacaine-polymer microspheres and examine whether they can produce prolonged blockade of the sciatic nerve in rats. METHODS: Microspheres were prepared using polylactic-co-glycolic acid polymers loaded with 75% w/w bupivacaine by a solvent evaporation method. Bupivacaine release from microspheres was determined in vitro by ultraviolet spectroscopy and scintillation counting. Sensory and motor blockade of the rat sciatic nerve were assessed in vivo after injection of microsphere suspensions. RESULTS: Depending on the type of microspheres, the dose, and the additive used, mean duration of sciatic nerve block ranged from 10 h to 5.5 days. Incorporation of 0.05% w/w dexamethasone into the microspheres resulted in significant prolongation of block (up to 13-fold), and only preparations that contained dexamethasone produced blocks lasting beyond 1 day. Bupivacaine was released in a controlled manner in vitro. Dexamethasone does not substantially slow bupivacaine release from microspheres in vitro. CONCLUSIONS: Prolonged percutaneous blockade of peripheral nerves is feasible. The recovery from blockade is complete, and plasma bupivacaine levels are far below the range associated with systemic toxicity. The mechanisms underlying the dexamethasone block-prolonging effect are under investigation.

Anesthetics, Local↗
PubMed1996

Glucocorticoids prolong rat sciatic nerve blockade in vivo from bupivacaine microspheres.

BACKGROUND: Previous work showed that incorporation of dexamethasone (0.05 weight/weight percentage) into bupivacaine microspheres prolonged blockade by eight to 13 times compared with that produced by bupivacaine microspheres alone. The determinants of dexamethasone's block-prolonging effect were examined and reported here. METHODS: Polylactic-co-glycolic acid polymer microspheres (65/35) with 75 weight/weight percentage bupivacaine were prepared. Microspheres were injected adjacent to the rat sciatic nerve, and sensory and motor blockade were assessed. A procedure was developed to test drugs for block-prolonging ability in vivo by placing test drugs in the injection fluid along with a suspension of bupivacaine microspheres. RESULTS: Dexamethasone alone in suspension did not produce blockade, nor did it prolong blockade induced by aqueous bupivacaine. Bupivacaine microspheres (150 mg drug/kg rat weight) produced blockade for 6 to 10 h. Dexamethasone in the suspending solution of microspheres prolonged block by up to five times. Glucocorticoids prolonged block in proportion to glucocorticoid/antiinflammatory potency. The corticosteroid antagonist cortexolone inhibited dexamethasone's blockade-prolonging action. Durations of blockade with or without dexamethasone were unaltered by hydroxyurea-induced neutrophil depletion. Microspheres were extracted from rats at time points ranging from 7 h to 7 days, and residual microsphere dry weight and bupivacaine content were similar in groups of rats injected with either bupivacaine microspheres or bupivacaine microspheres containing dexamethasone, respectively. CONCLUSIONS: Glucocorticoids prolong blockade from bupivacaine microspheres. The mechanism appears unrelated to the kinetics of bupivacaine release in vivo.

Anesthetics, Local↗
PubMed1996

[Use of digital luminescence radiography in voiding cystourethrography].

PURPOSE: Optimization of image quality by use of digital luminescence radiography (DLR) in voiding cystoureterography (VCU) instead of a conventional screen film system. PATIENTS AND METHODS: 53 patients with a suspected vesicouretral reflux were examined with a VCU in analogous and digital technique. The X-rays were taken in a sitting position while simultaneously measuring the bladder pressure. An intraindividual comparison was omitted for X-ray saving reasons. In the follow-up 3 patients were examined with the other system. Two radiologists and two urologists compared 60 VCU of 53 patients--30 VCU in conventional screen film and 30 in DLR technique presented in standard and edge-enhanced images--with regard to image quality according to 3-step score (A--good image quality, B--sufficient image quality, C--insufficient image quality). RESULTS: The 59 conventional films were scored 72 times with an A, 76 times with a B, and 72 times with a C, whereas the DLR films were scored 116 times with an A, 72 times with a B, and only 8 times with a C. Hereby the edge-enhanced images were the most useful for distinguishing the bladder shadow from the soft tissue of the thigh and for detecting reflux. Furthermore, the exposure dose when applying DLR could be decreased to 75% in grown-ups and to 57% in children without any significant loss of information. CONCLUSION: The DLR is highly superior to the conventional film screen system because of its relatively high tolerance towards wrong exposures, especially with respect of the sitting position during MCU. With the DLR we obtained 96% and with the conventional system only 63% films usable for diagnosis.

Adolescent↗
PubMed1996

[Contrast medium behavior of epithelial skin tumors and tumor-like changes in high resolution magnetic resonance tomography].

To evaluate the use of Gd-DTPA in imaging epithelial skin tumors and tumor-like lesions, 29 benign, 8 malignant and 4 semimalignant skin tumors were prospectively examined by high-resolution MRI at 1.5 Tesla using a 2.5-cm surface coil. For tumor assessment, transverse plain and contrast-enhanced scans (0.1 mmol Gd-DTPA/kg body mass) were performed (TR 500 ms, TE 25 ms, 3 acquisitions, 256 x 256 matrix, FOV 2.5 cm). Contrast enhancement was quantitively determined as the percent enhancement of signal intensity. Histologic findings were correlated using the Mann-Whitney-test (p < 0.05). Quality of contrast enhancement was independently assessed by three investigators, who mostly described inhomogeneous enhancement, regardless of histologic findings. Malignant tumors could not be differentiated from benign lesions by contrast enhancement. MRI using Gd-DTPA does not provide differentiation of skin tumor types.

Adolescent↗
PubMed1996

[Spiral-CT of the liver: optimizing contrast medium administration and examination technique].

AIM OF STUDY: To analyze different protocols for spiral-CT with regard to the enhancement of liver parenchyma and vessels of the upper abdomen. To compare the achieved density values with those obtained by conventional CT. METHODS: 30 CT-examinations of the abdomen of different patients with normal findings of the liver were selected. In all examinations the upper abdomen was scanned before injection of contrast agent in conventional technique. In 10 patients spiral-CT of the liver was performed in the arterial phase at a delay of 15 sec and a flow of 4 ml/sec with 100 ml contrast agent, in 10 other patients in the portal-venous phase at a delay of 35 sec and a flow of 4 ml/sec with 100 ml contrast agent, followed by a spiral-CT of the upper abdomen in the arterial-venous phase at a delay of 70 sec and a flow of 1 ml/sec with 85 ml contrast agent. In 10 patients conventional CT of the upper abdomen was performed at a delay of 30 sec and a flow of 1 ml/sec with 200 ml contrast agent. RESULTS: The highest density of the aorta was achieved by the arterial spiral-CT (p < 0.001). In the portal-venous spiral-CT the density of liver parenchyma was lower than in the arterial-venous spiral-CT and conventional CT (p < 0.001). Both arterial-venous spiral-CT and conventional CT achieved the same contrast in the aorta (216 +/- 10 vs. 217 +/- 23 HE) and in liver parenchyma (110 +/- 3 vs. 112 +/- 16 HE), but arterial-venous spiral-CT showed a lower density in the inferior vena cava than conventional CT (138 +/- 9 vs. 162 +/- 21 HE) (p < 0.002). CONCLUSIONS: The spiral-CT-protocol for the examination of the liver in arterial and arterial-venous phase enables a reliable and adequate enhancement of liver parenchyma and all vessels of the upper abdomen with a lower dose of contrast agent than is possible with conventional CT. Together with unenhanced CT, this protocol promises a better detection of focal lesions of the liver with different enhancement modes in the arterial and venous phases.

Adult↗
PubMed1996

Strategies for stabilising tetanus toxoid towards the development of a single-dose tetanus vaccine.

The stability of tetanus toxoid (TT) has been investigated for the purpose of enhancing its immunogenicity when encapsulated in TT-polylactide-co-glycolide (PLGA) microspheres. In this paper we describe our simulations of various potential inactivating events during microsphere processing and release of the antigen. These include: i) processing aqueous TT solutions in the presence of organic solvents, ii) exposing lyophilized TT to moisture, and iii) incubating vaccine with the degrading PLGA. At 37 degrees C, TT began to aggregate in solution a few hours after the addition of either methylene chloride or ethyl acetate to form a single oil-water interface. Similarly, exposure of the lyophilized vaccine to elevated humidity caused the antigen to lose solubility. Previous analysis of moisture-induced aggregates has revealed that formaldehyde, which is stored in labile linkages in the vaccine following its detoxification, is the precursor to the reactive species in the principal aggregation pathway [1]. Methods to inhibit this mechanism, such as blocking nucleophilic amino groups of TT with succinic anhydride, were verified. Succinylation of TT resulted in the incorporation of 10-fold greater antigenically active vaccine in PLGA microspheres relative to the unmodified TT following processing by double-emulsion/solvent evaporation with ethyl acetate, strongly suggesting the formaldehyde-mediated aggregation pathway also occurs during the deleterious conditions of microsphere processing. Incubation of solutions of TT in the presence of excess blank (unloaded) poly (D,L) lactide (mol. wt. 2000) microspheres led to a dramatic reduction in pH (approximately 3.2 units after one day at 45 degrees C) and simultaneous precipitation of TT. Stabilisation in the presence of the degrading polymer is likely to be the final obstacle before controlled-release preparations can be formulated to release antigenically active TT over extended time periods. Hence, mechanistic analyses as described here may be crucial for the development of effective single-dose vaccines.

Delayed-Action Preparations↗
PubMed1996

Hemorheology, plasma protein composition and von Willebrand factor in type I diabetic nephropathy.

Patients with IDDM, especially those with albuminuria are at high risk for macrovascular and microvascular complications. Besides the major classic risk factors altered hemorheology may also play a role. Plasma viscosity, erythrocyte aggregation and erythrocyte deformability are the major determinants of blood flow in the microcirculation. Therefore, these hemorheological parameters and plasma protein composition were evaluated in 58 IDDM-patients with none (N0), incipient (N1: albuminuria 30-300 mg/day) and overt clinical nephropathy (N2: albuminuria > 300 mg/day). As an estimate of endothelial injury plasma levels of von Willebrand Factor (vWF) were investigated. Patients with incipient and clinical nephropathy exhibited increasing blood levels of fibrinogen (N0 = 2.47 +/- 0.09, N1 = 2.71 +/- 0.15, N2 = 3.49 +/- 0.24 g/l, p < 0.001), alpha 2-macroglobulin (N0 = 257 +/- 11, N1 = 251 +/- 21, N2 = 382 +/- 43 mg/100 ml, p < 0.01) and haptoglobin (N0 = 174 +/- 16, N1 = 216 +/- 39, N2 = 278 +/- 36 mg/100 ml, p < 0.05), whereas serum albumin concentration decreased (N0 = 5.1 +/- 0.1, N1 = 4.7 +/- 0.1, N2 = 4.1 +/- 0.2 g/100 ml, p < 0.001). In the same patients erythrocyte aggregation (N0 = 10.0 +/- 0.4, N1 = 12.1 +/- 0.5, N2 = 12.9 +/- 0.6, p < 0.001), plasma viscosity (N0 = 1.34 +/- 0.01, N1 = 1.38 +/- 0.02, N2 = 1.40 +/- 0.02 mPas, p < 0.05) and erythrocyte rigidity (N0 = 0.05 +/- 0.01, N1 = 0.15 +/- 0.05, N2 = 0.09 +/- 0.02, p < 0.05) were increased, predominantly in those with overt clinical nephropathy. Erythrocyte aggregation was positively correlated with plasma concentrations of fibrinogen (r = 0.65, p < 0.001) and alpha 2-macroglobulin (r = 0.35, p < 0.05), but negatively with plasma albumin concentration (r = -0.49, p < 0.001). Plasma viscosity was positively correlated with plasma concentrations of fibrinogen (r = 0.46, p < 0.001) and haptoglobin (r = 0.46, p < 0.001). Von Willebrand Factor levels were higher in patients with overt clinical nephropathy (N0 = 126 +/- 8, N1 = 136 +/- 12, N2 = 163 +/- 14%, p < 0.09, PN0-N2 < 0.05). A significant correlation between vWF and the rheological determinants could not be detected. These data demonstrate that blood rheology is profoundly altered in patients with IDDM and nephropathy. Elevated levels of vWF may indicate endothelial damage, and changes in plasma viscosity as well as erythrocyte aggregability seem to be the result of altered plasma protein composition due to proteinuria. These abnormalities in hemorheology may be an aggravating factor promoting microvascular and macrovascular damage in patients with type I diabetes mellitus and nephropathy.

Adult↗
PubMed1996

The use of scopolamine in the treatment of detrusor instability.

PURPOSE: A prospective randomized double-blind study was done to evaluate the efficiency of transdermal scopolamine in the treatment of detrusor instability. MATERIALS AND METHODS: A total of 20 female patients with detrusor instability was assigned randomly into 2 groups of 10 each. The study group received 4 transdermal scopolamine dermal patches postauricularly, while in the control group placebo patches were applied. Both groups were similar regarding patient age, parity, duration of symptoms and previous anti-incontinence surgery. RESULTS: The patients were reassessed after 14 days. Improvement in complaints of diurnal frequency (p < 0.05), nocturia (p < 0.005), urgency (p < 0.05) and urge incontinence (p < 0.05) was noted in the study group and not in the control group. A significantly (p < 0.05) less pressure increase on filling and a decreased volume at which pressure exceeded 15 cm. water (p < 0.05) were noted on cystometry in the study group only. No significant side effects were reported and no patient discontinued treatment. CONCLUSIONS: Transdermal scopolamine was effective and safe in the treatment of female patients with detrusor instability.

Administration, Cutaneous↗
PubMed1996

[Radiologic skeletal diagnosis: traumatology of the distal forearm, the wrists and the hand].

Plain X-ray films including some special radiographic views are still the basis of the radiological evaluation of injuries of the distal forearm, the wrist, and the hand. Especially in the diagnosis of fractures of the distal radius the exact positioning of the arm and hand is essential. For the description of fractures of the distal forearm the AO classification of fractures should be used, which is comprehensive and universally applicable. Conventional tomography and computed tomography (CT) of the radio-ulnar joint and the wrist are used in patients with persisting complaints or equivocal findings on plain radiographs, and difficult anatomical situations. Suspected ligamentous injuries of the wrist including tears of the triangular fibrocartilage complex (TFCC) are evaluated by wrist arthrography or magnetic resonance imaging (MRI), the latter requiring a highly skilled imaging and interpretation technique. MRI is the method of choice for the detection of osteonecrosis. Ultrasound examination are of minor importance in the work up of wrist and hand injuries.

Arthrography↗
PubMed1996

[Lipid peroxidation and hemolysis in HES cryopreserved erythrocytes].

Using malondialdehyde (MDH) as an indicator of lipid peroxidation it was examined, whether oxygen radicals could be an origin of freeze-induced weakness of HES-cryopreserved erythrocytes. Each of 11 erythrocyte suspensions (Hct = 40; HES 200,000/0.62/12.5%; 60 mmol NaCl) was separated into 40 ml samples, cooled down to -196 degrees C und stored at -80 degrees C, finally. Samples were thawed after 1, 2, 3 und 6 months storage and besides that, one sample having remained at -196 degrees C (LN2). The MDH content (1.5 mumol/l Ery unwashed; 0.4 mumol/l Ery washed) amounted to 3.4 mumol/l Ery after LN2 storage, to 4 mumol/l Ery after 1 und to 8 mumol/l Ery after 6 months at -80 degrees C. Similarly, the MDH generation rate at -80 degrees C increased with storage time. The membrane fragility (1 in freshly drawn erythrocytes; 1.3 in erythrocytes out of LN2) rose from 1.6 after 1 month to 2.4 after 6 months. MDH content and membrane fragility were correlated linearly (r = 0.98). It is concluded that increased superoxide formation is mediated by freezed-induced oxidation of Hb-bound Fe. This allows peroxidation of membrane lipids which in consequence causes hemolysis.

Blood Preservation↗
PubMed1996

[Storage-induced rheologic and biochemical changes in erythrocyte concentrates with added solution and possible correlations].

Rheological integrity is one of the essentials for red blood cells (rbc) in capillary circulation. The influences of metabolical/biochemical changes of rbc on their rheological properties are well known, but (to our knowledge) until now there are no published studies, which cover both quality aspects of packed rbc (prbc) in additive solutions. According to our standard operating procedures (SOP) we prepared prbc in additive solution (SAG-M) and plasma from 16 regular blood donations. The buffy coat was discharged. Following parameters were measured on day 1, 14 and 28: extracellular pH, ATP and 2,3-DPG content of rbc, prbc-viskosity, -filterability, -aggregability and filter clogging rate. For examination of the filterability a 5% rbc-suspension in phoshate buffered solution was prepared, the remaining tests were performed with rbc-samples adjusted to a hematokrit of 40% with fresh frozen autologous plasma. In correlation with the depletion of ATP a decrease of rbc flexibility and changes of shape (for example spherocytosis) are well known from the literature. Our results confirm the assumed time dependent deterioration of rheological patterns of prbc in SAG-M, reflecting in an increase of rbc-viscosity and filter clogging rate and a decrease of rbc-filterability and -aggregability. We also observed the expected decrease of pH, ATP and 2,3-DPG during storage. The influences of biochemical changes on rheological alterations are discussed. Therefore we recommend on demand rheological examinations in addition to metabolical/biochemical analyses for an extended quality assurance program, for instance for testing new additive solutions or major changes of SOP.

2,3-Diphosphoglycerate↗
PubMed1996

[Elimination of hydroxyethyl starch after autologous retransfusion of cryopreserved erythrocytes].

In the case of the biodegradable cryoprotectant hydroxyethyl starch (HES) no deglycerolization process is required prior to the transfusion of frozen red blood cells (RBC). In a first study the elimination of an HES 200,000/0.62 from the plasma of 6 dogs was investigated by means of a novel HPLC-GFC method. 16% of the blood volume were replaced by autologous HES protected frozen/thawed RBC. In a second study the HES concentration in the plasma of 7 healthy volunteers was determined following the substitution of 8% of the blood volume, but a washing step has been performed to reduce the concentration of the cryoprotectant (HES 200,000/0.5). In a third study, however, this step was omitted. The elimination of the HES followed always first order kinetics. In the case of the transfusions without postthaw washing in dogs and humans, the initial plasma concentrations amounted to 2.11 +/- 0.15 g/dl and 0.75 +/- 0.26 g/dl, respectively. The corresponding value for the washed preparations was less than 0.03 g/dl. Within 4-5 h the concentrations dropped to less than 50% of the initial values. The 9-hour value was less than 35% (dogs), the 20-hour value about 15% (humans) of the initial concentration. As HES is primarily eliminated via the kidneys, within this period the concentrations of HES in the urine dropped from 4.3 +/- 2.11 g/dl to less than 0.03 g/dl (humans, no washing step). In conclusion, the elimination of the accompanying cryoprotectant HES was no problem in the concentrations applied. A simple washing step with isotonic saline, however, effectively reduced the concentration of the extracellular cryoprotectant HES far below critical levels.

Animals↗
PubMed1996

[Value of percutaneous catheter cholangiography in postoperative biliodigestive and bilio-biliary anastomoses].

AIM OF STUDY: To examine the relative importance of percutaneous catheter cholangiography in postoperative diagnostics after biliary reconstruction. METHODS: 55 patients (33 males, 22 females) were subjected to 101 catheter cholangiographies. 30-50 ml of a water-soluble, iodic contrast medium were administered via an infusion system. Initial examinations were performed between the 3rd and 7th day following operation, while follow-up examinations were executed between the 8th and 145th day after surgery. The position of the catheter, the function of the anastomosis, the filling of the biliary ducts and the discharge of the contrast medium were assessed. RESULTS: 45 examinations were inconspicuous. Drainage obstruction of the contrast medium was observed in 24 cases. Filling defects were observed in 8 examinations. A dislocation of the catheter was encountered in 5 cholangiographies while 19 examinations displayed a bile leak. CONCLUSION: Percutaneous catheter cholangiographies can be used to detect postoperative complications following biliary reconstruction in an easy, reliable, and cost-effective manner that also does not put too much strain on the patient. Indications for the implementation of catheter cholangiographies are the occurrence of abdominal complaints, the clinical appearance of a peritonitis, or an increase of the serum bilirubin value. Routine examinations are recommended in conditions following liver transplantations. In addition to this, a cholangiography should be carried out prior to the removal of the catheter.

Adult↗
PubMed1995

Stabilization of tetanus and diphtheria toxoids against moisture-induced aggregation.

The progress toward single-dose vaccines has been limited by the poor solid-state stability of vaccine antigens within controlled-release polymers, such as poly(lactide-co-glycolide). For example, herein we report that lyophilized tetanus toxoid aggregates during incubation at 37 degrees C and elevated humidity--i.e., conditions relevant to its release from such systems. The mechanism and extent of this aggregation are dependent on the moisture level in the solid protein, with maximum aggregation observed at intermediate moisture contents. The main aggregation pathway is consistent with formaldehyde-mediated cross-linking, where reactive electrophiles created and stored in the vaccine upon formalinization (exposure to formaldehyde during vaccine preparation) react with nucleophiles of a second vaccine molecule to form intermolecular cross-links. This process is inhibited by the following: (i) succinylating the vaccine to block reactive amino groups; (ii) treating the vaccine with sodium cyanoborohydride, which presumably reduces Schiff bases and some other electrophiles created upon formalinization; and (iii) addition of low-molecular-weight excipients, particularly sorbitol. The moisture-induced aggregation of another formalinized vaccine, diphtheria toxoid, is also retarded by succinylation, suggesting the generality of this mechanism for formalinized vaccines. Hence, mechanistic stability studies of the type described herein may be important for the development of effective single-dose vaccines.

Bacterial Vaccines↗
PubMed1995

Fourier-transform infrared spectroscopic investigation of protein stability in the lyophilized form.

Upon the removal of water, proteins undergo a major, reversible rearrangement of their secondary structure, as revealed by FTIR spectroscopy. We have found herein that for recombinant human albumin (rHA) the extent of this structural change does not depend significantly either on the composition of the aqueous solution prior to lyophilization (protein concentration, pH, and the presence of excipients such as dextran or NaCl) or on the mode of dehydration (lyophilization, spray drying, or rotary evaporation), even though these factors profoundly affect rHA's solid-state stability against moisture-induced aggregation. In all cases, the alpha-helix content of rHA drops from 58% in solution to 25-35% in the dehydrated state, the beta-sheet content rises from 0 to 10-20%, and unordered structures increase from 40% to 50-60%. We have also investigated another model protein, hen egg-white lysozyme, and confirmed that it too undergoes a significant alteration of the secondary structure upon lyophilization. The extent of this structural reorganization has been found to be insensitive to the pH of the aqueous solution prior to lyophilization from pH 1.9 to 5.1, even though the thermal transition temperature (Tm) in aqueous solution over this range varies by 30 degrees C.

Dextrans↗
PubMed1995

Heparinase I from Flavobacterium heparinum: the role of the cysteine residue in catalysis as probed by chemical modification and site-directed mutagenesis.

Heparinase I (heparin lyase I, EC 4.2.2.7), a heparin-degrading enzyme produced by Flavobacterium heparinum, is used to deheparinize blood following extracorporeal procedures in surgery and in other applications. The present study of mapping and characterization of the cysteines of heparinase I represents the first structural characterization of a heparinase. [3H]Iodoacetic acid labeling demonstrated that heparinase I has two free cysteines. One of the two cysteines is surface accessible and lies in a hydrophilic environment while the other is in a hydrophobic environment. Chemical modification of the cysteines, both in the presence and in the absence of heparin, suggests that the surface-accessible cysteine lies in or near the active site of heparinase I. Preferential reactivity of this cysteine with negatively charged sulfhydryl-modifying reagents and the cysteines' high reactivity to iodoacetic acid at pH 6.5 indicate that the surface-accessible cysteine is in a positively charged region. The surface-accessible cysteine (cysteine-135) was mapped as the active-site cysteine by radiolabeling with [3H]iodoacetic acid and by tryptic digestion and peptide sequencing. Site-directed mutagenesis of cysteine-135 to a serine or an alanine in r-heparinase I demonstrates that this cysteine is essential for enzymatic activity. However, replacement of the surface-inaccessible cysteine by a serine or alanine has no effect.

Base Sequence↗