[Right adrenal recurrence of pheochromocytoma discovered 24 years after ablation of two ectopic pheochromocytomas]. / Nouvelle localisation surrénale droite d'un phéochromocytome découverte 24 ans après l'exérèse de deux phéochromocytomes ectopiques.

The classical localisation of chromaffin cell tumours is intra-adrenal. Ectopic or multiple tumours are not rare and are commonly observed in children. The authors report a case of ectopic pheochromocytoma with a double localisation in a 14 year old child (renal pedicle and right retropleural space), in which surgical ablation resulted in an immediate and sustained correction of the hypertension. Hypertension recurred 24 years later and a classical right adrenal pheochromocytoma was demonstrated by methyl-iodo-benzylguanidine (M.I.B.G.) scintigraphy and abdominal CT scan. Right adrenalectomy resulted in normalisation of the hypertension once again without antihypertensive therapy with a follow-up of three years. Regular follow-up is necessary after ablation of a pheochromocytoma, especially in children, even in the absence of a phacomatosis or multiple endocrine neoplastic syndromes.

[Comparison of coronary angiography by the left radial and right femoral approach with 4 French catheters]. / Comparaison de la coronarographie par voie radiale gauche et fémorale droite avec des sondes 4 french.

The radial arterial approach has been shown to be valuable for coronary angioplasty. The aim of this study was to evaluate the use of the left radial and right femoral approaches for diagnostic coronary angiography. The authors performed a prospective non-randomised series of consecutive diagnostic coronary angiogrammes with small calibre (4 french) catheters by the left radial (100 patients) and right femoral (100 patients) arteries. The feasibility, results and complications were compared. The study showed that diagnostic coronary angiography with 4 F catheters is feasible with a high success rate, both from the left radial (99%) and right femoral (100%) approaches (NS). The duration of the procedure tends to be longer when the radial approach is used (19.2 +/- 1.3 min) than by the femoral artery (16.3 +/- 1.1 min) (p = 0.06). The duration of irradiation is longer with the radial approach (6.7 +/- 1.2 vs 4.9 +/- 0.9 min) (p = 0.0001). Local complications are minor by either approach (N = 5 vs N = 6 patients; p = NS), and there were no major complications. The tolerance of the procedure was not as good when the radial artery was used (N = 5) compared with the femoral artery (N = 1 patient) because of arterial spasm when the catheters were changed. The authors conclude that the left radial and right femoral arteries can be used routinely for diagnostic coronary angiography with small catheters (4 French). The left radial approach allows immediate mobilisation of the patient but the duration of the procedure and the exposure to irradiation are longer.

[Hospital results of salvage angioplasty with coronary stenting after failure of thrombolysis in the acute phase of myocardial infarction]. / Résultats hospitaliers de l'angioplastie de sauvetage avec implantation d'endoprothèses coronaires après échec de thrombolyse à la phase aiguë de l'infarctus du myocarde.

Between December 1991 and February 19999, 25 patients (56 +/- 10 years) underwent salvage angioplasty with coronary stenting after failure of thrombolysis (TIMI 2), rtPA (N = 18), n-PA (N = 4), K2-tu-PA (N = 2) and streptokinase (N = 1). All were treated by aspirin and 96% were given ticlopidine for one month. The culprit artery was the left anterior descending (48%), the left circumflex (8%) or the right coronary (44%). The average ejection fraction was 41%; 4 patients (16%) had cardiogenic shock. The stents were implanted for occlusive coronary dissection (36%), threatening dissection (40%), partial result of angioplasty (20%) or of first intention (4%). In all, 31 stents were implanted (1.2 +/- 0.57 stent/target lesion ratio with an average length of 20.9 +/- 10.2 mm). The stents were tabular in 51% of cases. The angiographic success rate (TIMI 3 and residual stenosis < 50%) was 96% with maximum inflation pressures of 13.7 +/- 2.5 atm and balloons with an average diameter of 3.3 +/- 0.5 mm. Intra-aortic balloon pumping was required in 7 patients (28%). The 30 day results included a mortality rate of 16% (4 patients), a recurrence of infarction in 4%; there were no repeat angioplasties, coronary bypass surgery or blood transfusions. The predictive factors of recurrent coronary events were: age over 60 (p = 0.04), multivessel coronary disease (p = 0.007), cardiogenic shock (p = 0.004) and left ventricular dysfunction (p = 0.015). The authors conclude that cases of failure of thrombolysis are at high risk and that salvage angioplasty with coronary stenting is associated with excellent angiographic results. Patients with cardiogenic shock, however, have a high mortality, irrespective of coronary patency and the use of intra-aortic balloon pumping.

PLGA microparticles with zero-order release of the labile anti-Parkinson drug apomorphine.

The treatment of patients suffering from advanced Parkinson's disease is highly challenging, because the efficacy of the "gold standard" levodopa declines with time. Co-administration of the dopamine receptor agonist apomorphine is beneficial, but difficult due to the poor oral bioavailability and short half-life of this drug. In order to overcome these restrictions, PLGA-based microparticles allowing for controlled parenteral delivery of this morphine derivative were prepared using (solid-in-)oil-in-water extraction/evaporation techniques. Particular attention was paid to minimize spontaneous oxidation of the labile drug and to optimize the key features of the microparticles, including encapsulation efficiency, initial burst release and particle size. Various formulation and processing parameters were adjusted in this respect. The systems were thoroughly characterized using SEM, EDX, DSC, laser diffraction, headspace-GC as well as in vitro drug release measurements in agitated flasks and flow-through cells. Importantly, apomorphine could effectively be protected against degradation during microparticle preparation and within the delivery systems upon exposure to phosphate buffer pH 7.4 (containing 0.2% ascorbic acid) at 37 °C: 90% intact drug was released at a constant rate during about 10d.

PLGAs bearing carboxylated side chains: novel matrix formers with improved properties for controlled drug delivery.

Novel PLGA derivatives bearing carboxylated side chains have been synthesized and used to encapsulate the fragile drug apomorphine HCl with a solid-in-oil-in-water solvent extraction/evaporation method. Blends of d,l-lactide and l-3-(2-Benzyloxycarbonyl)Ethyl-1,4-Dioxane-2,5-dione (BED) were co-polymerized at different ratios via ring-opening using benzyl alcohol as initiator. Optionally, the ester groups in the side chains as well as the terminal ester groups were hydrogenolyzed (leading to free COOH groups). For reasons of comparison, different types of "conventional" PLGAs were also synthesized and used for apomorphine HCl encapsulation. The polymers and microparticles were thoroughly characterized using SEC, (1)H NMR, DSC, SEM, X-ray and laser diffraction, Headspace-GC as well as in vitro drug release measurements in flow-through cells and agitated flasks. Importantly, microparticles based on the new polymers bearing carboxylic groups in the polymeric side chains: (i) allowed a significant reduction of the amount of residual solvent (dichloromethane), and (ii) provided different types of drug release patterns compared to microparticles based on "conventional" PLGAs (at least partially due to altered polymer degradation kinetics). Thus, they offer an interesting potential as novel matrix formers in controlled drug delivery systems, overcoming potential shortcomings of standard PLGAs.

Impact of the experimental conditions on drug release from parenteral depot systems: From negligible to significant.

The aim of this study was to evaluate the impact of the experimental conditions on drug release measurements from parenteral depot systems. Frequently applied setups were used, including agitated and "non-agitated" flasks and tubes, flow-though cells as well as agarose gels. The bulk fluid volumes and flow rates were varied. Lipid implants (prepared by direct compression or melting & casting) as well as PLGA-based microparticles (prepared by O/W or W/O/W or S/O/W solvent extraction/evaporation methods) were studied. Theophylline, lidocaine, prilocaine, propranolol HCl, dexamethasone and ibuprofen were used as model drugs at different initial loadings. In all cases, the release medium was phosphate buffer pH 7.4, kept constant at 37°C. Particle size analysis, SEM, X-ray diffraction, DSC analysis and mathematical modeling were applied to better understand the observed phenomena. Interestingly, the importance of the impact of the experimental conditions ranged from negligible to significant, depending on the specific type of drug delivery system and setup. Both, lipid implants as well as PLGA-based microparticles can exhibit more or less sensitive/robust drug release patterns. The observed differences in sensitivity could partially be explained in a mechanistic way, but in many cases they are not yet fully understood. A thorough understanding of the underlying drug release mechanisms can be very helpful. If the devices are poorly characterized and treated as "black boxes", great care must be taken when drawing conclusions from in vitro drug release measurements.

Unintended potential impact of perfect sink conditions on PLGA degradation in microparticles.

Yet, no standardized test method for drug release measurements from PLGA-based microparticles has been generally agreed on, or described by the regulatory authorities. Often, perfect sink conditions are provided in vitro to avoid artificial drug saturation effects. However, the maintenance of such conditions might strongly affect PLGA degradation. The involved physicochemical processes are complex and the potential impact of perfect sink conditions is not yet well understood. Differently sized, highly porous, carbamazepine- and ibuprofen-loaded PLGA microparticles were prepared by a W/O/W emulsion solvent extraction/evaporation technique. The initial drug loading was intentionally low (3-4%) so that the two drugs were molecularly dispersed within the polymeric matrices (monolithic solutions). This was important to be able to exclude potential limited drug solubility effects on the resulting release kinetics. Drug release into phosphate buffer pH 7.4 was measured under perfect sink conditions. SEC, DSC and SEM were used to characterize polymer degradation. The decrease in the average polymer molecular weight, glass transition temperature as well as changes in the inner and outer morphology of the PLGA microparticles were strongly affected by the bulk fluid's volume. In the case of the poorly water-soluble drug carbamazepine, much lower "microparticle mass:phosphate buffer volume" ratios were required to maintain perfect sink conditions, resulting in stable pH values within the bulk fluid, slower PLGA degradation and, thus, lower drug release rates. Thus, great care has to be taken when defining the conditions for in vitro drug release measurements from PLGA-based microparticles, avoiding potentially artificial conditions for polymer degradation.