Improving screening and brief intervention activities in primary health care: Secondary analysis of professional accuracy based on the AUDIT-C.

INTRODUCTION AND OBJECTIVE: The ODHIN trial found that training and support and financial reimbursement increased the proportion of patients that were screened and given advice for their heavy drinking in primary health care. However, the impact of these strategies on professional accuracy in delivering screening and brief advice is underresearched and is the focus of this paper. METHOD: From 120 primary health care units (24 in each jurisdiction: Catalonia, England, the Netherlands, Poland, and Sweden), 746 providers participated in the baseline and the 12-week implementation periods. Accuracy was measured in 2 ways: correctness in completing and scoring the screening instrument, AUDIT-C; the proportion of screen-negative patients given advice, and the proportion of screen-positive patients not given advice. Odds ratios of accuracy were calculated for type of profession and for intervention group: training and support, financial reimbursement, and internet-based counselling. RESULTS: Thirty-two of 36 711 questionnaires were incorrectly completed, and 65 of 29 641 screen-negative patients were falsely classified. At baseline, 27% of screen-negative patients were given advice, and 22.5% screen-positive patients were not given advice. These proportions halved during the 12-week implementation period, unaffected by training. Financial reimbursement reduced the proportion of screen-positive patients not given advice (OR = 0.56; 95% CI, 0.31-0.99; P < .05). CONCLUSION: Although the use of AUDIT-C as a screening tool was accurate, a considerable proportion of risky drinkers did not receive advice, which was reduced with financial incentives.

Isoeffective dose: a concept for biological weighting of absorbed dose in proton and heavier-ion therapies.

When reporting radiation therapy procedures, International Commission on Radiation Units and Measurements (ICRU) recommends specifying absorbed dose at/in all clinically relevant points and/or volumes. In addition, treatment conditions should be reported as completely as possible in order to allow full understanding and interpretation of the treatment prescription. However, the clinical outcome does not only depend on absorbed dose but also on a number of other factors such as dose per fraction, overall treatment time and radiation quality radiation biology effectiveness (RBE). Therefore, weighting factors have to be applied when different types of treatments are to be compared or to be combined. This had led to the concept of 'isoeffective absorbed dose', introduced by ICRU and International Atomic Energy Agency (IAEA). The isoeffective dose D(IsoE) is the dose of a treatment carried out under reference conditions producing the same clinical effects on the target volume as those of the actual treatment. It is the product of the total absorbed dose (in gray) used and a weighting factor W(IsoE) (dimensionless): D(IsoE)=D×W(IsoE). In fractionated photon-beam therapy, the dose per fraction and the overall treatment time (in days) are the two main parameters that the radiation oncologist has the freedom to adjust. The weighting factor for an alteration of the dose per fraction is commonly evaluated using the linear-quadratic (α/ß) model. For therapy with protons and heavier ions, radiation quality has to be taken into account. A 'generic proton RBE' of 1.1 for clinical applications is recommended in a joint ICRU-IAEA Report [ICRU (International Commission on Radiation Units and Measurements) and IAEA (International Atomic Energy Agency). Prescribing, recording and reporting proton-beam therapy. ICRU Report 78, jointly with the IAEA, JICRU, 7(2) Oxford University Press (2007)]. For heavier ions (e.g. carbon ions), the situation is more complex as the RBE values vary markedly with particle type, energy and depth in tissue.

Patient specific treatment planning for systemically administered radiopharmaceuticals using PET/CT and Monte Carlo simulation.

The efficacy of systemically administered radiopharmaceuticals depends on the physiological path of the targeting molecule and the physical characteristics of the attached radionuclide. NM404 is a candidate for patient specific dosimetry because it can be used concurrently for both diagnosis and therapy. Radiolabeling NM404 with [(124)I] affords the possibility of performing noninvasive PET imaging while [(131)I] allows for radiotherapy. Patient specific dosimetry for radiation treatment planning for NM404 uses serial PET/CT data and Monte Carlo. [(124)I]NM404 PET helps to determine the organ at risk by which the maximum injected activity of [(131)I]NM404 will depend. The subsequent work uses a software interface (SCMS) to convert patient PET/CT data of a liver metastasis into a Monte Carlo environment for radiation transport analysis. Thereby, the dosimetry within the liver and tumor during both diagnostic and therapeutic procedures was determined. The results showed that per MBq injected of [(124)I] and [(131)I], the tumor receives an average of 1.2 and 1.5mGy, respectively, while the liver receives 0.031 and 0.022mGy, respectively.

Maximum proton kinetic energy and patient-generated neutron fluence considerations in proton beam arc delivery radiation therapy.

Several compact proton accelerator systems for use in proton therapy have recently been proposed. Of paramount importance to the development of such an accelerator system is the maximum kinetic energy of protons, immediately prior to entry into the patient, that must be reached by the treatment system. The commonly used value for the maximum kinetic energy required for a medical proton accelerator is 250 MeV, but it has not been demonstrated that this energy is indeed necessary to treat all or most patients eligible for proton therapy. This article quantifies the maximum kinetic energy of protons, immediately prior to entry into the patient, necessary to treat a given percentage of patients with rotational proton therapy, and examines the impact of this energy threshold on the cost and feasibility of a compact, gantry-mounted proton accelerator treatment system. One hundred randomized treatment plans from patients treated with IMRT were analyzed. The maximum radiological pathlength from the surface of the patient to the distal edge of the treatment volume was obtained for 180 degrees continuous arc proton therapy and for 180 degrees split arc proton therapy (two 90 degrees arcs) using CT# profiles from the Pinnacle (Philips Medical Systems, Madison, WI) treatment planning system. In each case, the maximum kinetic energy of protons, immediately prior to entry into the patient, that would be necessary to treat the patient was calculated using proton range tables for various media. In addition, Monte Carlo simulations were performed to quantify neutron production in a water phantom representing a patient as a function of the maximum proton kinetic energy achievable by a proton treatment system. Protons with a kinetic energy of 240 MeV, immediately prior to entry into the patient, were needed to treat 100% of patients in this study. However, it was shown that 90% of patients could be treated at 198 MeV, and 95% of patients could be treated at 207 MeV. Decreasing the proton kinetic energy from 250 to 200 MeV decreases the total neutron energy fluence produced by stopping a monoenergetic pencil beam in a water phantom by a factor of 2.3. It is possible to significantly lower the requirements on the maximum kinetic energy of a compact proton accelerator if the ability to treat a small percentage of patients with rotational therapy is sacrificed. This decrease in maximum kinetic energy, along with the corresponding decrease in neutron production, could lower the cost and ease the engineering constraints on a compact proton accelerator treatment facility.

Contribution to Neutron Fluence and Neutron Absorbed Dose from Double Scattering Proton Therapy System Components.

Proton therapy offers low integral dose and good tumor comformality in many deep-seated tumors. However, secondary particles generated during proton therapy, such as neutrons, are a concern, especially for passive scattering systems. In this type of system, the proton beam interacts with several components of the treatment nozzle that lie along the delivery path and can produce secondary neutrons. Neutron production along the beam's central axis in a double scattering passive system was examined using Monte Carlo simulations. Neutron fluence and energy distribution were determined downstream of the nozzle's major components at different radial distances from the central axis. In addition, the neutron absorbed dose per primary proton around the nozzle was investigated. Neutron fluence was highest immediately downstream of the range modulator wheel (RMW) but decreased as distance from the RMW increased. The nozzle's final collimator and snout also contributed to the production of high-energy neutrons. In fact, for the smallest treatment volume simulated, the neutron absorbed dose per proton at isocenter increased by a factor of 20 due to the snout presence when compared with a nozzle without a snout. The presented results can be used to design more effective local shielding components inside the treatment nozzle as well as to better understand the treatment room shielding requirements.

The RBE issues in ion-beam therapy: conclusions of a joint IAEA/ICRU working group regarding quantities and units.

This paper summarises the conclusions of a working group established jointly by the International Atomic Energy Agency (IAEA) and the International Commission on Radiation Units and Measurements (ICRU) to address some of the relative biological effectiveness (RBE) issues encountered in ion-beam therapy. Special emphasis is put on the selection and definition of the involved quantities and units. The isoeffective dose, as introduced here for radiation therapy applications, is the dose that delivered under reference conditions would produce the same clinical effects as the actual treatment in a given system, all other conditions being identical. It is expressed in Gy. The reference treatment conditions are: photon irradiation, 2 Gy per fraction, 5 daily fractions a week. The isoeffective dose D(IsoE) is the product of the physical quantity absorbed dose D and a weighting factor W(IsoE). W(IsoE) is an inclusive weighting factor that takes into account all factors that could influence the clinical effects like dose per fraction, overall time, radiation quality (RQ), biological system and effects. The numerical value of W(IsoE) is selected by the radiation-oncology team for a given patient (or treatment protocol). It is part of the treatment prescription. Evaluation of the influence of RQ on W(IsoE) raises complex problems because of the clinically significant RBE variations with biological effect (late vs. early) and position in depth in the tissues which is a problem specific to ion-beam therapy. Comparison of the isoeffective dose with the equivalent dose frequently used in proton- and ion-beam therapy is discussed.

In vitro cytotoxicity of mitoxantrone-incorporated albumin microspheres on acute promyelocytic leukaemia cells.

In the present study, the preparation and characterization of bovine serum albumin (BSA) microspheres and the evaluation of the in vitro cytotoxicity of these microspheres on acute promyelocytic leukaemia (HL-60) cells were described. Mitoxantrone (MTZ)-incorporated microspheres were evaluated for particle size, drug loading, release characteristics and surface morphology. The biological effect of MTZ released from BSA microspheres was determined on an in vitro cultured HL-60 cell line, showing that, after encapsulation, MTZ still retains cytotoxic activity. For this purpose, methyl-thiazol-tetrazolium (MTT) assay was used to evaluate the in vitro cytotoxicity of MTZ-loaded microspheres. Particle size of BSA microspheres was determined between 17.61-20.38 microm and they were smooth and spherical in shape. Encapsulation efficiency of the drug-loaded microspheres was between 22.26-60.50%. For MTZ-containing microspheres, the cell death ratios were greater than 80% for all formulations. This study demonstrate that BSA microspheres were well suited for the controlled release of MTZ and were promising for anti-cancer chemotherapy.

Measurement of the tissue to A-150 tissue equivalent plastic kerma ratio at two p(66)Be neutron therapy facilities.

The ICRU tissue to A-150 tissue equivalent plastic kerma ratio is needed for neutron therapy dosimetry. The current ICRU protocol for neutron dosimetry recommends using a common conversion factor of 0.95 at all high-energy neutron therapy facilities. In an effort to determine facility specific ICRU tissue to A-150 plastic kerma ratios, an experimental approach was pursued. Four low pressure proportional counters that differed in wall materials (i.e. A-150, carbon, zirconium and zirconium-oxide) were used as dosimeters and integral kerma ratios were determined directly in the clinical beam. Measurements were performed at two p(66)Be facilities: iThemba LABS near Cape Town and Fermilab near Chicago. At the iThemba facility the clinical neutron beam is routinely filtered by a flattening and hardening filter combination. The influence of beam filtration on the kerma ratio was evaluated. Using two recent gas-to-wall dose conversion factor (r(m,g) value) evaluations a mean ICRU tissue to A-150 plastic kerma ratio of 0.93 +/- 0.05 was determined for the clinical beam at iThemba LABS. The respective value for the Fermilab beam is 0.95 +/- 0.05. The experimentally determined ICRU tissue to A-150 plastic kerma ratios for the two clinical beams are in agreement with theoretical evaluations. Beam filtration reduces the kerma ratio by 3 +/- 2%.

Return to fertility after extended chemical castration with a GnRH antagonist.

BACKGROUND: Antagonistic analogues of GnRH for the treatment of prostate cancer may be used clinically in persons for whom return to fertility after such treatment is important or desirable. The purpose of this study was, therefore, to evaluate the effects of a long term treatment with orntide, a GnRH antagonist, on testosterone levels and fertility in male rats. METHODS: Two groups of male rats received either 120-day orntide microspheres (8.8 mg orntide/kg/120 days) or vehicle alone (control group). Serum orntide and testosterone levels in both groups were monitored at certain intervals for 9 months from the initiation of treatment. After recovery of normal serum testosterone levels in the treated animals, each rat was housed with two proven breeder, but drug-naive, females. RESULTS: All mates of treated rats achieved pregnancy as rapidly as the mates of control rats although two of the control rats did not sire a litter with either female and one sired only one litter. The mean size of the litters of treated (12.3 offspring per litter) and control (10.6 offspring per litter) were similar. All offspring were grossly normal morphologically and behaviorally during the time to weaning. CONCLUSIONS: These results suggest that lack of fertility due to testosterone suppression is reversible after cessation of treatment with this GnRH antagonist.

Comparison of the posterior approach versus the dorsal approach in the treatment of congenital vertical talus.

The purpose of this study was to compare retrospectively the results of a single-stage dorsal approach versus the posterior approach for the surgical treatment of congenital vertical talus (CVT) at a single institution. Twenty-four patients (33 feet) with CVT were treated surgically between 1960 and 1998. Eighteen patients (25 feet) underwent a posterior release (group 1), and six patients (eight feet) underwent surgery via the dorsal approach (group 2). All patients were evaluated at a minimal follow-up of 3 years. Preoperative and follow-up radiographs were evaluated, and a modified version of the clinical score by Adalaar was used. Group 1 had 45 procedures on 25 feet, whereas group 2 had no repeated or revision operations. The clinical score was 6.75 for group 1 and 8.0 for group 2. Tourniquet time was 123 minutes and 87 minutes for groups 1 and 2, respectively. Twelve group 1 patients (48%) had avascular necrosis (AVN) versus none of the group 2 patients. Both groups had similar preoperative and postoperative radiographic measurements. Both approaches were able to reduce successfully the talonavicular joint; however, the single-stage dorsal incision group required significantly less operative time, had better clinical scores, and had fewer complications 3 years after surgery.

Skeletal effects of parathyroid hormone (1-34) in ovariectomized rats with or without concurrent administration of salmon calcitonin.

This study evaluated the effect of parathyroid hormone (PTH) infusion alone or in combination with salmon calcitonin (sCT) in ovariectomized (OVX) rats and compared it with daily PTH injections alone or in combination with sCT infusion. Female Sprague-Dawley rats were divided randomly into 6 groups and were either bilaterally ovariectomized or underwent a sham operation; they were then treated for 4 weeks, beginning the day after surgery. Each group of OVX rats received either PTH infusion (group 1), PTH + sCT infusion (group 2), sCT infusion + daily PTH injection (group 3), or daily PTH injection (group 4). One group each of OVX (group 5) and sham-operated rats (group 6) received daily injections of vehicle alone. PTH was injected at 80 microg/kg/day and infused at 40 microg/kg/day, whereas sCT was infused at 10 microg/kg/day. The animals were sacrificed 28 days after treatment, and cancellous bone volume was measured in the tibial metaphysis. Similar to daily PTH injections, continuous infusion of PTH alone increased cancellous bone volume significantly over that seen in vehicle-treated OVX and sham-operated rats. Although cancellous bone volume after continuous infusion of PTH + sCT was also significantly higher than that seen in vehicle-treated OVX and sham-operated rats, the increase was significantly lower than with the other 3 nonvehicle treatments. The increase in cancellous bone volume after administration of sCT infusion along with daily PTH injections was not different from that with daily PTH injections alone. Thus, at the doses tested, the beneficial effects of PTH injection were not apparently improved by PTH infusion or by combination with sCT.

Preparation, characterization, and in vitro evaluation of 1- and 4-month controlled release orntide PLA and PLGA microspheres.

PURPOSE: To prepare, characterize and evaluate in vitro sustained delivery formulations for a novel LHRH antagonist, Orntide acetate, using biodegradable microspheres (ms). METHODS: Poly(d,l-lactide) (PLA) and poly(d,l-lactide-co-glycolide) (PLGA) were characterized for molecular weight (Mw, Mn) using gel permeation chromatography (GPC) and content of free end carboxyl groups (acid number, AN) by a titration method. 1- and 4-month Orntide ms were prepared by a dispersion/solvent extraction/evaporation process and characterized for drug content (HPLC), bulk density (tapping method), particle size (laser diffraction method), surface morphology (scanning electron microscopy, SEM), and structural integrity of encapsulated peptide by Fourier Transform Matrix Assisted Laser Desorption mass spectrometry (FT-MALDI). Peptide binding to PLA and PLGA and non-specific adsorption to blank ms was studied in 0.1 M phosphate buffer pH 7.4 (PB) and 0.1 M acetate buffer pH 4.0 (AB). In vitro release of peptide was assessed in PB and AB. RESULTS: Mw for the PLGA copolymers varied from 10,777 to 31,281 Da and was 9,489 Da for PLA. AN was between 4.60 and 15.1 for the hydrophilic resomers and 0.72 for the hydrophobic 50:50 PLGA copolymer. Spherical ms (3.9 mu to 14 mu in diameter) with mostly nonporous surface and varying degree of internal porosity were prepared. FT-MALDI mass spectra of the extracted peptide showed that the encapsulation process did not alter its chemical structure. Peptide binding to PLGA and PLA and non-specific adsorption to blank PLGA ms were dependent upon pH and were markedly higher in PB than in AB. The initial in vitro release in PB varied from 0.5 to 26%/24 h but due to substantial binding of the peptide to the polymeric matrix the long-term release in PB could not be determined. Application of a dialysis method allowed for a more accurate determination of in vitro release and a good total drug recovery. CONCLUSIONS: Orntide acetate was successfully incorporated into PLA and PLGA ms and the 1- and 4-month in vitro release profiles were achieved by polymer selection and optimization of the manufacturing parameters.

Effect of the concurrent LHRH antagonist administration with a LHRH superagonist in rats.

PURPOSE: The purpose of this study was to investigate the effect of a novel LHRH antagonist, Orntide acetate, on the initial testosterone elevation in rats during treatment with a LHRH superagonist, Leuprolide acetate. METHODS: Thirteen groups of a rat animal model were administered either liquid Orntide or Orntide PLGA microspheres before or simultaneously with Leuprolide injections. Serum levels of testosterone were monitored during the time course of the study using a radioimmunoassay method. RESULTS: Administration of a single daily dose of liquid Orntide resulted in testosterone suppression within 6 h to levels below 0.5 ng/ml (castration level). However, combined administration of liquid Orntide and liquid Leuprolide did not have a significant effect on the initial testosterone elevation in studied rats. Similarly, there was no effect when liquid Orntide was co-administered with Leuprolide microspheres. Administration of Orntide microspheres 48 h before Leuprolide microspheres suppressed testosterone levels below the castration level within 24 h, however, did not prevent a rise in testosterone serum concentration upon administration of Leuprolide microspheres. Also, a second testosterone peak was observed between days 3 and 15 in the animals which were simultaneously treated with Orntide microspheres and Leuprolide microspheres. CONCLUSIONS: Orntide acetate was found to be an effective LHRH antagonist with a rapid onset of pharmacological action and a short biological half-life. Administration of a single dose of liquid Orntide or Orntide microspheres, resulted in rapid testosterone suppression without an initial elevation, as seen with LHRH superagonists. However, combined administration of Orntide and Leuprolide did not have an effect on the initial testosterone elevation in rats.

Enhancing initial release of peptide from poly(d,l-lactide-co-glycolide) (PLGA) microspheres by addition of a porosigen and increasing drug load.

The objective of this study was to evaluate formulation variables such as drug load and addition of a porosigen in achieving an increased initial release of peptide from poly(d,l-lactide-co-glycolide) (PLGA) microspheres by altering carrier characteristics. Leuprolide acetate-loaded PLGA microspheres were prepared by a solvent-extraction-evaporation process and were characterized for their drug load (HPLC assay), bulk density (tapping method), size distribution (dynamic light scattering), specific surface area (Brunauer-Emmett-Teller [BET] analysis), surface morphology (scanning electron microscopy), in vitro drug release (at 37 degrees C), and in vivo efficacy (suppression of rat serum testosterone). Increasing the drug load, and adding various amounts of calcium chloride to organic and aqueous phases of the emulsion during processing yielded particles with increased porosity, lower bulk density, higher specific surface area, and accordingly higher initial release. In an animal model, these formulations showed a faster onset of testosterone suppression compared to microspheres without higher drug load or calcium chloride. The approaches employed in this study were found to be effective in avoiding the therapeutic lag phase usually observed with microencapsulated macromolecular drugs.

Experimental kerma coefficients and dose distributions of C, N, O, Mg, Al, Si, Fe, Zr, A-150 plastic, Al203, AlN, SiO2 and ZrO2 for neutron energies up to 66 MeV.

Low-pressure proportional counters (LPPCs) with walls made from the elements C, Mg, Al, Si, Fe and Zr and from the chemical compounds A-150 plastic, AlN, Al2O3, SiO2 and ZrO2 were used to measure neutron fluence-to-kerma conversion coefficients at energies up to 66 MeV. The LPPCs served to measure the absorbed dose deposited in the gas of a cavity surrounded by the counter walls that could be converted to the absorbed dose to the wall on the basis of the Bragg-Gray cavity theory. Numerically the absorbed doses to the walls were almost equal to the corresponding kerma values of the wall materials. The neutron fluence was determined by various experimental methods based on the reference cross sections of the 1H(n, p) scattering and/or the 238U(n, f) reactions. The measurements were performed in monoenergetic neutron fields of energies of 5 MeV, 8 MeV, 15 MeV and 17 MeV and in polyenergetic neutron beams with prominent peaks of energies of 34 MeV, 44 MeV and 66 MeV. For the measurements in the polyenergetic neutron beams, significant corrections for the contributions of the non peak energy neutrons were applied. The fluence-to kerma conversion coefficients of N and O were determined using the difference technique applied with matched pairs of LPPCs made from a chemical compound and a pure element. This paper reports experimental fluence-to-kerma conversion coefficient values of eight elements and four compounds measured for seven neutron energies, and presents a comparison with data from previous measurements and theoretical predictions. The distributions of the absorbed dose as a function of the lineal energy were measured for monoenergetic neutrons or, for polyenergetic neutron fields, deduced by applying iterative unfolding procedures in order to subtract the contributions from non-peak energy neutrons. The dose distributions provide insight into the neutron interaction processes.

A novel in vitro release technique for peptide containing biodegradable microspheres.

The purpose of this study was to develop and evaluate a dialysis in vitro release technique for peptide-containing poly(d, l-lactide-co-glycolide) (PLGA) microspheres (ms) that would correlate with in vivo data. Using a luteinizing hormone- releasing hormone analogue (LHRH), Orntide acetate, solubility and stability were determined in 0.1 M phosphate buffer (PB), pH 7.4, and in 0.1 M acetate buffer (AB), pH 4.0, with high-performance liquid chromotography (HPLC), and peptide permeability through a dialysis membrane (molecular weight cut-off 300,000) was determined. Orntide ms were prepared by a dispersion/solvent extraction/evaporation method and characterized for drug content (HPLC), particle size distribution (laser diffraction method), and surface morphology (scanning electron microscopy). In vitro release was studied in PB using a conventional extraction method and with a new dialysis method in AB. Gravimetric analyses of polymer mass loss and matrix hydration, and peptide adsorption to blank PLGA ms (50:50, M(w) 28 022) were carried out in PB and AB upon incubation at 37 degrees C. Serum Orntide and testosterone levels in rats after administration of Orntide ms were determined by radioimmunoassay. Orntide acetate solubility was influenced by pH; approximately 2.3 mg/mL dissolved in PB and > 18 mg/mL in AB. Stability was pH- and temperature-dependent. The peptide was very stable at pH 4.0, 4 degrees C, but degraded rapidly at pH 7.4, 37 degrees C. Peptide permeability through the dialysis membrane was accelerated by agitation and >95% equilibrium was reached within 48 hours. The overall release rate was higher with the dialysis method. Mass loss of the Orntide ms was faster in AB (50% loss in 3 weeks; 95% in 35 days) than in PB (65% in 35 days). In contrast, hydration after 35 days was 4-fold higher in PB. The nonspecific adsorption to blank ms was greater in PB (128 microg Orntide/10 mg PLGA) compared with AB (< 5 microg Orntide/ 10 mg PLGA). Administration of 30-day Orntide PLGA ms to rats resulted in an initial serum Orntide level of 21 ng/mL after 6 hours and a Cmax of 87 ng/mL after 6 days. Testosterone levels were suppressed immediately after ms administration (3 mg Orntide /Kg) from 5.2 ng/mL to 0.3 ng/mL (after 24 hours) and remained suppressed for 38 days. Orntide acetate solubility and degradation kinetics were markedly influenced by pH of the buffer systems and mass loss; matrix hydration, as well as the nonspecific adsorption to blank ms, was pH-dependent. The in vitro release profile obtained with the dialysis method in AB correlated well with the in vivo data, thereby providing a more reliable prediction of in vivo performance.

Evaluation of Orntide microspheres in a rat animal model and correlation to in vitro release profiles.

Orntide acetate, a novel luteinizing hormone-releasing hormone (LHRH) antagonist, was prepared and evaluated in vivo in 30-day and 120-day sustained delivery formulations using a rat animal model. Orntide poly(d,l-lactide-co-glycolide) (PLGA) and poly(d,l- lactide) (PLA) microspheres were prepared by a dispersion method and administered subcutaneously in a liquid vehicle to rats at 2.2 mg Orntide/kg of body weight (30-day forms) or 8.8 mg Orntide/kg (120-day forms). Serum levels of Orntide and testosterone were monitored by radioimmunoassays, and a dose-response study at 4 doses (3, 2.25, 1.5, and 1.75 mg Orntide/kg) was conducted to determine the effective dose of Orntide. Microspheres with diameters between 3.9 and 14 micron were prepared. The onset and duration of testosterone suppression varied for different microsphere formulations and were influenced both by polymer properties and by microsphere characteristics. Microspheres prepared with 50:50 and 75:25 copolymers effectively sustained peptide release for 14 to 28 days, whereas an 85:15 copolymer and the PLA microspheres extended the pharmacological response for more than 120 days. Increase in drug load generally accelerated peptide release from the microspheres, resulting in higher initial serum levels of Orntide and shorter duration of the release. In general, apparent release was faster in vivo than under in vitro conditions. Orntide microspheres effectively suppressed testosterone in rats, providing rapid onset of release and extended periods of chemical castration. Testosterone suppression occurred immediately after microsphere administration without the initial elevation seen with LHRH superagonists.

Arthroscopic treatment of patellar clunk.

Excellent results have been reported with posterior stabilized total knee arthroplasty. A common complication relating to patellofemoral articulation is patellar clunk syndrome. Patellar clunk syndrome occurs when a fibrous nodule develops just proximal to the patellar button. At approximately 30 degrees to 45 degrees from full extension, the nodule catches the anterior flange of the femoral prosthesis, resulting in the clunk and a painful range of motion. The present study examines the use of arthroscopic debridement for this disorder. Thirty consecutive patients (32 knees) with the diagnosis of patellar clunk syndrome were evaluated at 1 year after arthroscopic debridement. All patients were evaluated clinically and radiographically according to the Knee Society score. In addition, patients were questioned specifically regarding anterior knee pain and patellofemoral symptoms. Radiographs were evaluated further regarding patella and component position. Patients were diagnosed with patellar clunk at an average of 12 months after their latest knee arthroplasty, with a range of 3 to 47 months. All patients complained of anterior knee pain and the clunk. All patients had a hypertrophic nodule at the junction of the proximal pole of the patella and quadriceps tendon and underwent arthroscopic debridement through a superolateral portal. All patients were free of patellar clunk postoperatively; one patient reported persistent anterior knee pain. Knee Society scores increased from an average of 64 points preoperative to 93 points postoperative. Radiographs showed patella alta in eight knees, patella baja in two. Four femoral components were in 5 degrees flexion. The present study represents the largest collection of data regarding patellar clunk syndrome. The data appear to support arthroscopic debridement as a successful treatment of patellar clunk syndrome.

A consistent set of neutron kerma coefficients from thermal to 150 MeV for biologically important materials.

Neutron cross sections for nonelastic and elastic reactions on a range of elements have been evaluated for incident energies up to 150 MeV. These cross sections agree well with experimental cross section data for charged-particle production as well as neutron and photon production. Therefore they can be used to determine kerma coefficients for calculations of energy deposition by neutrons in matter. Methods used to evaluate the neutron cross sections above 20 MeV, using nuclear model calculations and experimental data, are described. Below 20 MeV, the evaluated cross sections from the ENDF/B-VI library are adopted. Comparisons are shown between the evaluated charged-particle production cross sections and measured data. Kerma coefficients are derived from the neutron cross sections, for major isotopes of H, C, N, O, Al, Si, P, Ca, Fe, Cu, W, Pb, and for ICRU-muscle, A-150 tissue-equivalent plastic, and other compounds important for treatment planning and dosimetry. Numerous comparisons are made between our kerma coefficients and experimental kerma coefficient data, to validate our results, and agreement is found to be good. An important quantity in neutron dosimetry is the kerma coefficient ratio of ICRU-muscle to A-150 plastic. When this ratio is calculated from our kerma coefficient data, and averaged over the neutron energy spectra for higher-energy clinical therapy beams [three p (68) + Be beams, and a d (48.5) + Be beam], a value of 0.94 +/- 0.03 is obtained. Kerma ratios for water to A-150 plastic, and carbon to oxygen, are also compared with measurements where available.

Influence of formulation parameters on the characteristics of poly(D, L-lactide-co-glycolide) microspheres containing poly(L-lysine) complexed plasmid DNA.

This study describes the influence of polymer type, surfactant type/concentration, and target drug loading on the particle size, plasmid DNA (pDNA) structure, drug loading efficiency, in vitro release, and protection from DNase I degradation of poly(D, L-lactide-co-glycolide) (PLGA) microspheres containing poly(L-lysine) (PLL) complexed pDNA. PLGA microspheres containing pDNA-PLL were prepared using the water-in-oil-in-water (w-o-w) technique with poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) as surfactants in the external aqueous phase. A complex ratio of 1:0.33 (pDNA-PLL, w/w) enhanced the stability of pDNA during microsphere preparation. Higher pDNA-PLL loading efficiency (46.2%) and supercoiled structure (64.9%) of pDNA were obtained from hydrophobic PLGA (M(w) 31000) microspheres compared with hydrophilic PLGA or low-molecular-weight PLGA microspheres. The particle size decreased from 6.6 to 2.2 microm when the concentration of PVA was increased from 1 to 7%. At the same concentration of surfactant, PVA stabilized microspheres showed higher pDNA-PLL loading efficiency (46.2%) than PVP stabilized microspheres (24.1%). Encapsulated pDNA in PLGA microspheres was protected from enzymatic degradation and maintained in the supercoiled form. The pDNA-PLL microspheres showed in vitro release of 95.9 and 84.9% within 38 days from the low-molecular-weight PLGA and hydrophilic PLGA microspheres, respectively, compared to 54.2% release from the hydrophobic, higher-molecular-weight PLGA microspheres. The results suggest loading and release of pDNA-PLL complex can be influenced by surfactant concentration and polymer type.