Mechanistic analysis of PLGA/HPMC-based in-situ forming implants for periodontitis treatment.

In-situ forming implant formulations based on poly(lactic-co-glycolic acid) (PLGA), acetyltributyl citrate (ATBC), minocycline HCl, N-methyl pyrrolidone (NMP) and optionally hydroxypropyl methylcellulose (HPMC) were prepared and thoroughly characterized in vitro. This includes electron paramagnetic resonance (EPR), nuclear magnetic resonance ((1)H NMR), mass change and drug release measurements under different conditions, optical microscopy, size exclusion chromatography (SEC) as well as antibacterial activity tests using gingival crevicular fluid samples from periodontal pockets of periodontitis patients. Based on these results, deeper insight into the physico-chemical phenomena involved in implant formation and the control of drug release could be gained. For instance, the effects of adding HPMC to the formulations, resulting in improved implant adherence and reduced swelling, could be explained. Importantly, the in-situ formed implants effectively hindered the growth of bacteria present in the patients' periodontal pockets. Interestingly, the systems were more effectively hindering the growth of pathogenic bacterial strains (e.g., Fusobacterium nucleatum) than that of strains with a lower pathogenic potential (e.g., Streptococcus salivarius). In vivo, such a preferential action against the pathogenic bacteria can be expected to give a chance to the healthy flora to re-colonize the periodontal pockets.

In-situ forming composite implants for periodontitis treatment: How the formulation determines system performance.

Periodontitis is the primary cause of tooth loss in adults and a very wide-spread disease. Recently, composite implants, based on a drug release rate controlling polymer and an adhesive polymer, have been proposed for an efficient local drug treatment. However, the processes involved in implant formation and the control of drug release in these composite systems are complex and the relationships between the systems' composition and the implants' performance are yet unclear. In this study, advanced characterization techniques (e.g., electron paramagnetic resonance, EPR) were applied to better understand the in-situ forming implants based on: (i) different types of poly(lactic-co-glycolic acid) (PLGA) as drug release rate controlling polymers; (ii) hydroxypropyl methylcellulose (HPMC) as adhesive polymer; and (iii) doxycycline or metronidazole as drugs. Interestingly, HPMC addition to shorter chain PLGA slightly slows down drug release, whereas in the case of longer chain PLGA the release rate substantially increases. This opposite impact on drug release was rather surprising, since the only difference in the formulations was the polymer molecular weight of the PLGA. Based on the physico-chemical analyses, the underlying mechanisms could be explained as follows: since longer chain PLGA is more hydrophobic than shorter chain PLGA, the addition of HPMC leads to a much more pronounced facilitation of water penetration into the system (as evidenced by EPR). This and the higher polymer lipophilicity result in more rapid PLGA precipitation and a more porous inner implant structure. Consequently, drug release is accelerated. In contrast, water penetration into formulations based on shorter chain PLGA is rather similar in the presence and absence of HPMC and the resulting implants are much less porous than those based on longer chain PLGA.

In situ forming implants for periodontitis treatment with improved adhesive properties.

Novel in situ forming implants are presented showing a promising potential to overcome one of the major practical hurdles associated with local periodontitis treatment: limited adhesion to the surrounding tissue, resulting in accidental expulsion of at least parts of the implants from the patients' pockets. This leads to high uncertainties in the systems' residence times at the site of action and in the resulting drug exposure. In the present study, the addition of different types and amounts of plasticizers (acetyltributyl citrate and dibutyl sebacate) as well as of adhesive polymers (e.g., cellulose derivatives such as hydroxypropyl methylcellulose) is shown to allow for a significant increase in the stickiness of poly(lactic-co-glycolic acid)-based implants. The systems are formed in situ from N-methyl pyrrolidone-based liquid formulations. Importantly, at the same time, good plastic deformability of the implants can be provided and desired drug release patterns can be fine-tuned using several formulation tools. The antimicrobial activity of this new type of in situ forming implants, loaded with doxycycline hyclate, was demonstrated using the agar well diffusion method and multiple Streptococcus strains isolated from the oral microflora of patients suffering from periodontitis.

Accelerated ketoprofen release from polymeric matrices: importance of the homogeneity/heterogeneity of excipient distribution.

Polymeric matrices loaded with 10-50% ketoprofen were prepared by hot-melt extrusion or spray-drying. Eudragit E, PVP, PVPVA and HPMC were studied as matrix formers. Binary "drug-Eudragit E" as well as ternary "drug-Eudragit E-PVP", "drug-Eudragit E-PVPVA" and "drug-Eudragit E-HPMC" combinations were investigated and characterized by optical macro/microscopy, SEM, particle size measurements, mDSC, X-ray diffraction and in vitro drug release studies in 0.1 M HCl. In all cases ketoprofen release was much faster compared to a commercially available product and the dissolution of the drug powder (as received). Super-saturated solutions were obtained, which were stable during at least 2 h. Importantly, not only the composition of the systems, but also their inner structure potentially significantly affected the resulting ketoprofen release kinetics: For instance, spray-drying ternary ketoprofen:Eudragit E:HPMC combinations led to a more homogenous HPMC distribution within the systems than hot-melt extrusion, as revealed by mDSC and X-ray diffraction. This more homogenous HPMC distribution resulted in more pronounced hindrance for water and drug diffusion and, thus, slower drug release from spray-dried powder compared to hot-melt extrudates of identical composition. This "homogeneity/heterogeneity effect" even overcompensated the "system size effect": the surface exposed to the release medium was much larger in the case of the spray-dried powder. All formulations were stable during storage at ambient conditions in open vials.

[Nuclear cardiology in the preoperative evaluation of the patient at risk of coronary disease; meta-analysis of the contribution of thallium dipyridamole scintigraphy]. / La cardiologie nucléaire dans l'évaluation préopératoire du patient à risque coronarien; méta-analyse de l'apport de la scintigraphie au thallium sous dipyridamole.

Coronary disease may be assessed by several techniques of nuclear cardiology: classical thallium myocardial scintigraphy, position scintigraphy, left ventricular angioscintigraphy. These techniques measure the response of coronary flow, myocardial metabolism, or left ventricular contractility during a physical or pharmacologic stress test. Many studies have reported the interest of dipyridamole thallium scintigraphy in the assessment of the surgical risk for a coronary event. Regarding the meta-analysis of up-to-day published studies, the surgical risk is 26% for an abnormal test against 3% for a normal study. Considering only the risk of infarction or cardiac death, corresponding probabilities are 18% and 2%, respectively. Dipyridamole stress test is a fairly safe and accurate method for discriminating between high and low risk patients in a population selected on clinical grounds.

[The concept of utility in decision strategies: application to diagnosis and treatment of renovascular hypertension]. / Le principe d'utilité dans la stratégie de décision: application au diagnostic et au traitement de l'hypertension rénovasculaire.

To select a guideline in the management of diagnosis and treatment of renovascular hypertension, the clinician has to take into account many contradictory elements. He has to weight the invasive nature and the relative accuracy of the diagnostic tests, as well as the efficacy and drawbacks of medical and surgical treatments. The concept of utility in a decision making tree may lead to objective determination of best suited management for a given patient, according to the prior probability he had a renovascular hypertension.

Emission tomography for assessment of diffuse alcoholic liver disease.

A method of quantitative liver tomoscintigraphy (SPECT) was compared for accuracy with planar scintigraphy (PS) in a group of patients with diffuse alcoholic liver disease. SPECT sensitivity was also compared with that of transmission computed tomography (CT), US, aminopyrine breath test (ABT) and liver chemistries (LC). One hundred and fourteen alcoholic patients with proven liver disease and 17 patients free of liver disease were included. Seven quantitative scintigraphic features and a score, including all criteria were considered. With a specificity of 95%, the sensitivity was 79% in steatosis and 97% in cirrhosis. SPECT showed a better sensitivity than PS (SPECT 89%, PS 66%), especially in patients with steatosis. In the same subsets of patients, SPECT sensitivity also compared favorably with that of transmission CT (SPECT 92%, CT 65%), ultrasonography (SPECT 88%, US 53%) and ABT (SPECT 90%, ABT 63%).

Lack of cardiovascular side effects of the new tricyclic antidepressant tianeptine. A double-blind, placebo-controlled study in young healthy volunteers.

In a double-blind, placebo-controlled, crossover study, the effects of therapeutic doses of the new tricyclic antidepressant tianeptine on cardiovascular function were closely monitored in 21 healthy volunteers during a 2-week treatment period. Blood pressure measurements, ECG recording, 24-h Holter monitoring, and echocardiography were carried out at 1-week intervals. Isotopic ventriculography was measured twice under each treatment. Tianeptine did not produce orthostatic hypotension or increase heart rate. No ECG changes could be observed and the cardiac conduction time remained unchanged. One subject presented with an increase in frequency of ventricular premature beats that could not be definitely attributed to the drug. Cardiac output assessed at rest and after a bicycle exercise stress test was not altered. The present study suggests that tianeptine is a tricyclic antidepressant endowed with less cardiac toxicity than classical tricyclic antidepressants.

[Reliability of scintigraphic methods in the diagnosis of coronary insufficiency]. / Fiabilité des méthodes scintigraphiques dans le diagnostic de l'insuffisance coronaire.

Some conceptual problems arise when applying the probability analysis to the scintigraphic diagnosis of coronary artery disease. Analysis with Bayes' rule considers disease to be present or absent, radionuclide test response to be positive or negative, sensitivity and specificity to be the same in all patients. In fact, disease can be graded in severity; test results can be analysed as continuous variables; sensitivity and specificity of our diagnostic procedures are not constants but depend of the population features. Moreover, the accuracy of the radionuclide tests refers to the coronary arteriogram, which is not the appropriate standard of coronary artery disease.

Measurement of right ventricular volumes from ECG-gated steady-state krypton-81m angiocardiography.

The physical characteristics of krypton-81m makes it particularly suited for the study of right ventricular function, but its ultrashort half-life (13.3 s) precludes in vitro measurements of blood pool specific activity needed for count based determination of ventricular volumes. A combined geometric count based method was developed to measure absolute right ventricular volumes during steady state krypton-81m angiocardiography: background corrected ventricular count rates were converted to volumes using a count to volume calibration factor calculated in an 'internal reference ROI' located in the right ventricular outflow tract. Stroke volumes calculated with this method were shown to be comparable to thermodilution determined stroke volumes and the ability of the method to monitor changes in right ventricular volumes was demonstrated during intervention studies.

Evaluation of the accuracy of steady-state krypton-81m method for calculating right ventricular ejection fraction.

The accuracy of a steady-state 81mKr method for calculating the right ventricular ejection fraction (RVEF) has been examined in this study. Causes of errors using this method and their effects on the calculated RVEF were evaluated. The results suggested that mixing in the right ventricle during continuous infusion of 81mKr was homogenous, allowing for the calculation of ejection fraction using the count rate ratio. Lung activity was quite important and could not be neglected in computing RVEF, but the use of [99mTc]MAA lung perfusion scanning seemed to allow a correct subtraction of this background activity. The delineation of right ventricular regions of interest (ROIs) was complicated by the translation movements of the right ventricle during heart contraction. These ROIs should be drawn carefully on the count density distribution images and data shown by parametric images; such as first and second harmonic phase, amplitude images, and composite stroke volume image should be considered. Furthermore, this study demonstrates the superiority of the 81mKr technique compared with 99mTc methods for computing RVEF. In conclusion, even if the true accuracy of the 81mKr method for calculating RVEF cannot be proven due to the lack of reference methods, strong, suggestive evidence that the technique should be accurate is shown here.

Right ventricular ejection fraction: comparison of technetium-99m first pass technique and ECG-gated steady state krypton-81m angiocardiography.

Right ventricular ejection fraction (RVEF) calculated from ECG-gated steady-state 81mKr angiocardiography and from 99mTc first-pass studies were compared in 30 patients using a digital, single crystal, gamma-camera. Despite the two entirely different approaches RVEF values obtained by the two methods were comparable (r = 0.97): the mean absolute difference between the two techniques was 2.5% +/- 1.5% and the largest observed absolute difference was 5%. In the absence of an accepted reference method for measuring RVEF, this close correlation provides indirect validation of both techniques. The choice of method will therefore depend on several factors, including radiotracer availability, the characteristics of the gamma-camera and the protocol of clinical investigation.

Measurement of glomerular filtration rate by means of a 99Tcm-DTPA complex and a scintillation camera: a method based on the kinetics of the distribution volume of the tracer in the kidney area.

Glomerular filtration rate (GFR) may be computed using the kinetics of the renal distribution volume curve Vt = Rt/Pt and a power fit of the plasma curve Pt = Pot-B. It can be demonstrated that GFR = d(Vt)/d(t)(1-B). The method is largely independent of background subtraction, allowing nonequivocal renal function determination in all cases. In a preliminary series of 20 patients, the linear regression coefficient of computed GFR with true clearance measurement by multiple blood samples method was 0.97 with a standard error on the estimate of the clearance of 5.5 ml.

Measurement of left-ventricular volumes using an internal standard.

When performing equilibrium radionuclide angiocardiography with two successive acquisition views, absolute left-ventricular volumes can be calculated using an 'internal standard' generated by a computer in the left-ventricular cavity. The method is based on the computed ratio of maximum to global activity in the 40 degree-left-anterior-oblique view after background correction and on the measured depth of the left ventricle in almost-orthogonal, 30 degree-left-posterior-oblique Fourier first-harmonic images. The method does not require blood sampling or correction for self attenuation. The intra- and interobserver reproducibility is excellent, even in patients with severe impairment of the ventricular-contractility pattern. When compared with a classical method requiring venous-blood counting and an attenuation correction factor, the accuracy of the internal-standard method was fairly good, with a regression coefficient of 0.90.

Tc-99m-MDP bone scanning detection of gastric calcification.

A 50-year-old man with hypercalcemia related to Cope syndrome was referred for bone scintigraphy. There was a clear accumulation of the technetium-phosphate complex in the stomach. The condition was reversible with treatment of the underlying cause.

Bacterial meningitis complicated by spinal arachnoiditis: diagnostic contribution of Tc-99m-inulin myeloscintigraphy.

Six cases of bacterial meningitis with myeloscintigraphic evidence of medullary arachnoiditis are reported. Four patients has tuberculous meningitis, another showed severe myelopathy, and the last was suspected to have hydrocephalus. Arachnoiditis is suspected when the earliest images show a sharp decrease of tracer concentration. Scintigraphy began 2 hours after lumbar injection of Tc-99m-Polyfructosan and imaging was performed at intervals of 2, 4, and 6 hours. This method has proved easy, innoculous, reproducible, and, owing to the small amount of irradiation, studies may be repeated during and after therapy. Scintigraphy is superior to the Queckenstedt test becaise it detects partial blocks and localizes lesions.