Rechargeable anticandidal denture material with sustained release in saliva.

OBJECTIVE: Candida-induced denture stomatitis is a common debilitating problem among denture wearers. Previously, we described the fabrication of a new denture material that released antifungal drugs when immersed in phosphate buffered saline. Here, we use more clinically relevant immersion conditions (human saliva; 37°C) and measure miconazole release and bioactivity. MATERIALS AND METHODS: Disks were prepared by grafting PNVP [poly(N-vinyl-2-pyrrolidinone)] onto PMMA [poly(methylmethacrylate)] using plasma initiation (PMMA-g-PNVP) and then loaded with miconazole. Drug-loaded disks were immersed in 10-100% human saliva (1-30 days). Miconazole release was measured and then tested for bioactivity vs miconazole-sensitive and miconazole-resistant Candida isolates. RESULTS: HPLC was used to quantify miconazole levels in saliva. Miconazole-loaded disks released antifungal drug for up to 30 days. Higher drug release was found with higher concentrations of saliva, and, interestingly, miconazole solubility was increased with higher saliva concentrations. The released miconazole retained its anticandidal activity. After immersion, the residual miconazole could be quenched and the disks recharged. Freshly recharged disks displayed the same release kinetics and bioactivity as the original disks. Quenched disks could also be charged with chlorhexidine that displayed anticandidal activity. CONCLUSIONS: These results suggest that PMMA-g-PNVP is a promising new denture material for long-term management of denture stomatitis.

Liquid dextran does not increase the elution rate of different antibiotics from bone cement.

PURPOSE: To investigate the possibility of increasing elution of fosfomycin, gentamicin, clindamycin, and vancomycin by the addition of dextran fluid during the cement-mixing phase. METHODS: In 12 test series, we produced standardized, antibiotic-loaded test specimens of cement, with and without addition of dextran, and determined their effectiveness against three reference pathogens in agar diffusion and elution tests. RESULTS: In the test series using combined agents, Refobacin(®)-Palacos(®)R plus fosfomycin continuously produced the largest zone of inhibition, both against methicillin-sensitive Staphylococcus aureus (p = 0.009) and against methicillin-resistant Staphylococcus aureus (p = 0.009). The addition of dextran to the various test series had no useful effect on the size of the zone of inhibition for any of the antibiotics tested. CONCLUSIONS: Dextran supplementation in Refobacin(®)-Palacos(®)R bone cement did not have the hope for positive effect on the elution rate of bound antibiotics.

Characterisation and toxicological behaviour of Basic Methacrylate Copolymer for GRAS evaluation.

Basic Methacrylate Copolymer is a fully polymerised cationic copolymer with taste-masking and moisture protection properties. It is used as a pharmaceutical excipient and has potential use as a glazing/coating agent to solid food supplements. This article describes available information on the safety of the substance. Oral administration of radiolabelled copolymer to rats showed the major route of excretion to be via the faeces. Minor absorption may occur at <0.02%. Safety studies revealed no adverse toxicity following repeated administration at up to 2000 mg/kg/day in a sub-chronic study in the rat or 750 mg/kg/day in a sub-acute study in the dog. No reproductive toxicity occurred at up to 1000 mg/kg/day in the rat. The substance shows no evidence of genotoxicity, has low acute toxicity and no irritation or sensitisation potential. As per the FDA approach an ADI of 20 mg/kg bw can be concluded. Daily exposure from use as a food additive is estimated as up to 11.7 mg/kg bw in adults and 13.3 mg/kg bw in children. In view of the high molecular weight of the substance, its lack of absorption and its low toxicity profile, the ADI is deemed adequate.

'To bead or not to bead?' Treatment of osteomyelitis and prosthetic joint-associated infections with gentamicin bead chains.

Gentamicin-containing polymethylmethacrylate (PMMA) beads are frequently used to prevent and treat orthopaedic infections. The beads are typically inserted to fill anatomical defects secondary to surgical debridement. Local gentamicin use results in low serum levels whilst achieving high concentrations at the site of infection. However, a systematic review of the available literature showed that, despite these theoretical advantages, no prospective study has thus far proven gentamicin-containing PMMA beads to be effective in treating orthopaedic infections. Available studies are based on small patient numbers and do not show significantly better results when local and parenteral antibiotics are combined compared with systemic therapy alone. These poor results may be explained partially by reduced aminoglycoside efficacy when biofilms or gentamicin-resistant bacteria are present. Moreover, little is known regarding the potential side effects of gentamicin-containing beads. In this paper, the pros and cons regarding the use of gentamicin-containing PMMA beads are discussed. It is concluded that more well-executed, prospective studies are needed to settle the discussion on the use of gentamicin-containing beads in the treatment of orthopaedic infections.

Tapioca starch graft copolymers and Dome Matrix modules assembling technology. I. Effect of module shape on drug release.

This paper studies the Riboflavin release from compressed disc modules of Dome Matrix(R) technology using tapioca starch-ethylmethacrylate (TSEMA) and tapioca hydroxypropylstarch-ethylmethacrylate (THSEMA), graft copolymers produced by two different drying methods. The comparison with the release behaviour of similar HPMC modules was performed. Two different shape modules have been made, identified as female and male modules, in order to obtain their assemblage by interlocking the disc bases. HPMC matrices showed quasi-linear Riboflavin release in case of both female and male modules, with faster drug release than TSEMA modules. In the case of THSEMA modules, a faster release was observed compared to HPMC modules. Furthermore, matrices obtained with TSEMA copolymers remained nearly intact after dissolution process, while matrices containing HPMC experimented a complete dissolution of the modules. Combining these results with the release curve analysis using the Korsmeyer and Peppas exponential equation, HPMC modules controlled the drug release by polymer relaxation or erosion. For TSEMA and THSEMA, the drug release mechanism was controlled mainly by drug diffusion. The pronounced faster releases for the matrices containing THSEMA copolymers compared with the ones with TSEMA were due to a more important erosive support; however, the main structure of the matrix remains coherent. Porosity and tortuosity values and the shape of the modules explained the drug release observed.

Concepts for increasing gentamicin release from handmade bone cement beads.

BACKGROUND AND PURPOSE: Commercial gentamicin-loaded bone cement beads (Septopal) constitute an effective delivery system for local antibiotic therapy. These beads are not available in all parts of the world, and are too expensive for frequent use in others. Thus, orthopedic surgeons worldwide make antibiotic-loaded beads themselves. However, these beads are usually not as effective as the commercial beads because of inadequate release kinetics. Our purpose was to develop a simple, cheap, and effective formulation to prepare gentamicin-loaded beads with release properties and antibacterial efficacy similar to the commercially ones. METHODS: Acrylic beads were prepared with variable monomer content: 100% (500 microL/g polymer), 75%, and 50% to increase gentamicin release through creation of a less dense polymer matrix. Using the optimal monomer content, different gel-forming polymeric fillers were added to enhance the permeation of fluids into the beads. Polyvinylpyrrolidone (PVP) 17 was selected as a suitable filler; its concentration was varied and the antibiotic release and antibacterial efficacy of these beads were compared with the corresponding properties of the commercial ones. RESULTS: Gentamicin release rate and the extent of release from beads prepared with 50% monomer increased when the PVP17 content was increased. Beads with 15 w/w% PVP17 released 87% of their antibiotic content. This is substantially more than the gentamicin release from Septopal beads (59%). Acrylic beads with 15 w/w% PVP17 reduced bacterial growth by up to 93%, which is similar to the antibacterial properties of the commercial ones. INTERPRETATION: A simple, cheap, and effective formulation and preparation process has been described for hand-made gentamicin-releasing acrylic beads, with better release kinetics and with antibacterial efficacy similar to that of the commercial ones.

Safeness of Simplex-tobramycin bone cement in patients with renal dysfunction undergoing total hip replacement.

PURPOSE: To compare the pharmacokinetic profile of tobramycin in blood, urine, and at the operative site following the use of Simplex-tobramycin bone cement in primary total hip replacement between patients with and without renal dysfunction. METHODS: Six patients with renal dysfunction underwent cemented primary total hip replacement for osteoarthritis. The elution characteristics of Simplex-tobramycin bone cement in the 6 patients with renal dysfunction were compared with 9 patients who had normal renal function. Blood, urine, and drainage fluid specimens were collected for 72 hours postoperatively. RESULTS: Very high concentrations of tobramycin were seen in the drainage fluid of the 2 groups. Mean serum tobramycin levels peaked at postoperative 3 hours, and declined rapidly to negligible levels at 72 hours in both groups. Mean urinary tobramycin concentrations peaked at postoperative 12 hours and declined rapidly until 48 hours in both groups. Urinary tobramycin was excreted significantly more slowly in renal dysfunction group in the first 12 hours, but not thereafter. Although serum creatinine levels of the renal dysfunction group were higher throughout the study period, the difference was not significant. Both groups achieved excellent local delivery of the antibiotic with minimal systemic concentrations. CONCLUSION: Simplex-tobramycin bone cement appears to be an effective and safe means to deliver antibiotic for patients with renal dysfunction who undergo total hip replacement.

[Characterization of custom-made biomaterials containing antibiotics]. / Charakterisierung arzneimittelhaltiger Biomaterialien als kundenspezifische Sonderanfertigung.

The aim of this study was to evaluate the quality of custom-made antibiotic carriers which are produced for hospitals in a central service laboratory. These sterile products, made according to antibiogram, showed quality parameters which are comparable with commercially available products in terms of antibiotic release and other relevant properties.

The pharmacokinetics of Simplex-tobramycin bone cement.

We prospectively investigated a consecutive series of ten patients undergoing a cemented primary total hip replacement (THR) for osteoarthritis in order to establish the elution characteristics of Simplex-tobramycin bone cement (Howmedica, Limerick, Ireland). Specimens of blood, urine and drainage fluid were collected for 72 hours postoperatively. Very high concentrations of tobramycin were found in the drainage fluid, with mean levels at one hour of 103 mg/l, which steadily declined to 15.1 mg/l after 48 hours. The mean serum tobramycin levels reached a peak of 0.94 mg/l at three hours and declined rapidly to 0.2 mg/l by 48 hours. The mean urinary tobramycin levels peaked at 57.8 mg/l at 12 hours with a rapid decline to 12.6 mg/l by 24 hours. There was a direct correlation between the amount of tobramycin bone cement which was implanted and the amount of tobramycin systemically absorbed. Excellent local delivery was achieved with minimal systemic concentrations. Simplex-tobramycin bone cement is an efficient and safe method for the delivery of antibiotics after THR.

In vitro release of gentamicin from OHAp/PEMA/PMMA samples.

The influence of hydroxyapatite (OHAp) and gentamicin sulphate (GEN) contents on the release kinetics of GEN, in samples composed of OHAp, poly(methyl methacrylate) (PMMA) and poly(ethyl methacrylate) (PEMA) has been studied. For this purpose, samples with 30 and 40% of OHAp and 5 and 9% of GEN were prepared. The in vitro release study was carried out soaking the samples in simulated body fluid (SBF) at 37 degrees C for 70 days. The release profiles showed a faster release during the first 10 h, diminishing progressively until the end of the study. It was noticed that the percentage of released GEN increased with the OHAp content. For samples with 40% of OHAp, GEN release is nearly independent of the initial amount of such drug (in the range 5-9%), whereas for samples with 30% of OHAp, the release process is favoured by higher contents of GEN, which would favour a higher SBF uptake. GEN release is related to SBF uptake, which is in turn related, on the one hand, to the OHAp content (increase of the porosity and the hydrophilic character of the samples) and on the other hand, to content of GEN.

The use of antibiotic-containing bead chains in the treatment of chronic bone infections.

The implantation of gentamicin polymethylmethacrylate (PMMA) chains or minichains into infected osteomyelitic cavities is a well-established local antibiotic therapy supplementary to radical debridement. The gentamicin concentrations achieved at the site of infection are far above the MICs for most common pathogens in chronic osteomyelitis. Serum and urine concentrations are low, and nephrotoxic and ototoxic side-effects of this form of gentamicin application are not to be feared. Under local antibiotic therapy with gentamicin PMMA chains, primary wound healing as in aseptic surgery can be expected. Prolonged systemic antibiotic therapy is unnecessary. In a series of 405 cases, a success rate of 90.4% was obtained.

Ex vivo degradation of a poly(propylene glycol-fumarate) biodegradable particulate composite bone cement.

We have developed a biodegradable particulate composite bone cement consisting of a poly(propylene glycolfumarate)-(methylmethacrylate) matrix mixed with calcium carbonate and tricalcium phosphate particulates. Previous ex vivo studies suggest that this system provides sufficient strength for a number of potential clinical applications including structural reinforcement of osseous defects, internal fixation devices for age-related fractures, and delivery of antibiotics to treat osteomyelitis. As a first step toward investigating in vivo responses to this material, we studied the influence of varied concentrations of crosslinker, accelerator, and free radical on the mechanical properties of the cement. We then developed an ex vivo degradation assay and correlated the mechanical properties of degrading cement with the temporal changes in chemical properties of both the cement and the bathing medium. The optimal cement formulation was composed of one-third poly(propylene glycolfumarate)-(methylmethacrylate), one-third calcium carbonate, and one-third tricalcium phosphate, and provided initial compressive strengths of up to 30 MPa and compressive moduli of up to 300 MPa. Degradation rates, measured by a decline in mechanical properties, dissolution of calcium from the cement, and change in pH of the bathing medium, could be controlled by changing the concentration of reactants in the matrix. Specifically, an increase in methylmeth-acrylate or increase in both methylmethacrylate and benzoyl peroxide was inversely proportional to the rate of degradation and directly proportional to the initial mechanical properties. The degradation products and environmental changes appear to be compatible with physiologic remodeling and therefore justify examination of the in vivo response to implantation of this material.

Methylmethacrylate and bone screw repair of seventh lumbar vertebral fracture-luxations in dogs.

Fracture-luxations of the seventh lumbar vertebrae in two large dogs were stabilised with bone screws and methylmethacrylate. Screws inserted bilaterally into the bodies of the lumbar vertebrae and ilial wings were left protruding by about 2 cm, and embedded in methylmethacrylate bone cement. Implant failure occurred in one dog six days after surgery, necessitating a revision of the fixation. Fracture healing and return of normal ambulation occurred in both dogs. Implants were removed in one dog because of screw loosening and discomfort.

[Use of mini-septopal in trauma surgery of the hand. Experimental and clinical studies]. / Zastosowanie mini-septopalu w chirurgii urazowej reki. badania doswiadczalne i kliniczne.

The antibiotics application in treatment of infections makes necessary that they are present in the focus of infection in concentration which is enough to fight back bacteria responsible for the symptoms of disease. Concentration higher then MIC is especially difficult to obtain in tissue with poor blood supply.c. in the cortical bone. Many attempts has been made to find proper method to obtain high antibiotic concentration in the infection focus without overloading the rest of the organism. In the years 1972-1973 Klemm in Frankfurt/Main had first very promising results treating bone infections by filling bone cavities after proper surgical debridement with hand-made beads made of bone cement with gentamicin. This method has been developed by the E. MERCK company which started to produce drug as Septopal. Very good results of treatment using this form of antibiotic created natural demand for this method also in hand surgery, where big sized Septopal beads couldn't be used. E. MERCK company has provided us with Septopal Mini Chains where small ellipsoids are gathered in 10- or 20 elements chains. Starting investigations on SMC application the following aims of experimental and clinical studies has been pointed out: observation of tissue reaction for the implanted ellipsoids, studies on gentamicin releasing velocity and its concentration in the implantation site as well as in the tissues of peripheral organs, observation of the potential toxicity and observation of the ellipsoids structure in the scanning electron microscopy, evaluation of usefulness of the SMC in the treatment of bone and soft tissue infections and in prophylactics in high risk wounds treatment, evaluation of its efficiency in comparison with gentamicin-resisted bacterial strains. Statistical analysis of results has proved very high efficiency of this form of drug by obtaining very high local antibiotic concentration even 100 times higher then after parenteral application. No toxic reactions has been noticed. In the Department of Traumatology Medical Academy in Wroclaw in the years 1983-1991 Septopal Mini Chains has been applied in 76 cases and very good results-complete healing has been obtained in 83% of patients. These data allow us to evaluate very high the usefulness of the Septopal Mini Chains as very good, new method of bone and soft tissue infection treatment in the area of hand.

Estudio de estabilidad de tabletas de liberación prolongada elaboradas a partir de polimetacrilato de quinidina / Study of the stability of sustained-release tablets produced from quinidine polymethacrylate

Se estudió la estabilidad de tabletas de liberación prolongada confeccionadas a partir de polimetacrilato de quinidina, mediante el control periódico de las características físicas químicas y los perfiles de liberación de la sustancia biológicamente activa en muestras envejecidas por diferentes métodos. Los resultados obtenidos demuestran que el producto analizado mantiene una estabilidad adecuada en condiciones normales de almacenamiento

Elution characteristics of gentamicin-PMMA beads after implantation in humans.

Seventeen patients had gentamicin-PMMA beads implanted for treatment of orthopedic infections. The authors found that beads implanted in patients for 3 to 36 weeks were capable of eluting high levels of antibiotic after retrieval. Beads that were implanted in patients for less than 10 weeks eluted significantly higher antibiotic levels than beads were implanted for more than 14 weeks. This study supports the local use of these beads in the treatment of musculoskeletal infections.

Antibiotic release from impregnated pellets and beads.

Antibiotic impregnated beads are being used increasingly in the initial treatment of open fracture wounds, producing high antibiotic levels locally, over the first few days. Pellets were prepared to assess the release of the following antibiotics: benzylpenicillin, flucloxacillin, amoxycillin, amoxycillin-clavulanate (Co-Amoxiclav), ciprofloxacin, imipenem, or gentamicin; the carrier material was either polymethylmethacrylate (PMMA) or plaster of Paris (PoP). Elution of antibiotic over 72 hours from the pellets in vitro was determined using an agar-diffusion microbiologic assay. The initial rapid release of antibiotic lasted 12-24 hours, with release from PoP pellets at least four-fold greater than that from corresponding PMMA pellets. A second phase consisted of a sustained but gradually diminishing elution. The release of antibiotics from PoP pellets compared favorably with that from the PMMA beads currently used. We conclude that PoP pellets may be particularly suitable for short-term applications such as infection prophylaxis in open fractures.

Sodium fluoride sustained-release bone cement: an experimental study in vitro and in vivo.

A new "low temperature" bone cement, consisting of polymethylmethacrylate (PMMA) and 6% sodium fluoride, was developed for use in orthopedics. Fluoride is a well-known agent that may stimulate osteoblast activity and differentiation in vitro and in vivo; for this reason fluoride has been used for 30 years in the treatment of osteoporotic diseases of the bone. A local effect obtained with a slow release of fluoride from bone cement at the interface between bone and prosthetic implants could potentially enhance new bone formation around the prosthesis. This material was investigated both "in vitro", by establishing the kinetics of fluoride release from the acrylic bone cement and its maximal compressive strength, and "in vivo", by fitting 24 rabbits, which were then killed after 4, 12 and 16 weeks, with femoral implants, following labelling with fluorescent stains to allow the histologic evaluation of bone remodelling. The "in vitro" study revealed the release kinetics of fluoride from bone cement and the compressive strength of PMMA, that is not affected by the addition of fluoride. The "in vivo" investigation showed considerable healing ability after surgical and heat trauma, and new bone formation that appears larger on the surface in contact with fluoridated cement.

[Local antibiotic administration in osteomyelitis treatment--a comparative study with two different carrier substances]. / Lokale Antibiotika-Applikation in der Osteomyelitisbehandlung--Eine Vergleichsstudie mit zwei verschiedenen Trägersubstanzen.

Two antibiotic carriers (collagen sponge/PMMA-beads--loaded with gentamicin) for the treatment of osteomyelitis of long bones are compared in a randomised prospective study of 20 patients in respect of efficacy, safety and biocompatibility. In addition, the concentration of gentamicin in serum, urine and wound exudate was measured. This revealed marked differences. Gentamicin was released rapidly from the collagen sponge, leading to high levels in wound exudate and urine within the first 48 hours, with measurable but non-toxic concentrations in the serum. The liberation of gentamicin from the PMMA beads was much slower. This resulted in low steady levels in wound exudate and urine, and no detectable concentrations in the serum. The clinical outcome showed no differences between both methods of application. In 80% of the collagen sponge group and in 90% of the PMMA-beads group the osteomyelitis was completely allayed with disappearance of all infectious parameters. The number of re-operations was significantly higher in the PMMA group. It is recommended to use collagen sponges for the local treatment of osteomyelitis in cases that can probably be eradicated in a single surgical procedure, whereas PMMA beads should be applied in larger defects requiring a space-occupying function for further reconstructive operations.