Early Deformation of Deep Brain Stimulation Electrodes Following Surgical Implantation: Intracranial, Brain, and Electrode Mechanics

IntroductionAlthough deep brain stimulation is nowadays performed worldwide, the biomechanical aspects of electrode implantation received little attention, mainly as physicians focused on the medical aspects, such as the optimal indication of the surgical procedure, the positive and adverse effects, and the long-term follow-up. We aimed to describe electrode deformations and brain shift immediately after implantation, as it may highlight our comprehension of intracranial and intracerebral mechanics.Materials and MethodsSixty electrodes of 30 patients suffering from severe symptoms of Parkinson’s disease and essential tremor were studied. They consisted of 30 non-directional electrodes and 30 directional electrodes, implanted 42 times in the subthalamus and 18 times in the ventrolateral thalamus. We computed the x (transversal), y (anteroposterior), z (depth), torsion, and curvature deformations, along the electrodes from the entrance point in the braincase. The electrodes were modelized from the immediate postoperative CT scan using automatic voxel thresholding segmentation, manual subtraction of artifacts, and automatic skeletonization. The deformation parameters were computed from the curve of electrodes using a third-order polynomial regression. We studied these deformations according to the type of electrodes, the clinical parameters, the surgical-related accuracy, the brain shift, the hemisphere and three tissue layers, the gyration layer, the white matter stem layer, and the deep brain layer (type I error set at 5%).ResultsWe found that the implanted first hemisphere coupled to the brain shift and the stiffness of the type of electrode impacted on the electrode deformations. The deformations were also different according to the tissue layers, to the electrode type, and to the first-hemisphere-brain-shift effect.ConclusionOur findings provide information on the intracranial and brain biomechanics and should help further developments on intracerebral electrode design and surgical issues

Closure of an oroantral fistula by bone autograft: a case report

Introduction: The management of the oroantral fistula is mainly focused on th closure of the mucosa. The surgical management restoring the underlying bone defect are seldom. Maintaining this defect may compromise implant rehabilitation in this sector. The purpose of this article was to show, through a clinical case, an alternative way to manage an oroantral fistula and the bone tissue defect in the same time. Observation: After a rigourous clinical and radiological observation of a 2-year oroantral fistula, an impacted autologous bone graft of the maxillary tuberosity followed by a water tight closure of the mucosa, were realized in a 50-year old patient. Commentary: Using this surgical technique was successful for the closure of the mucosa as for the bone defect reconstruction. A consolidation was noticed and an pre-implant management and a dental implant placement could be realized. Conclusion: The choice of this surgical technique for the management of an oroantral fistua had a direct influence on the future prosthetic rehabilitation. The surgical technique presented for this case could be an interesting approach because the fixed or removable prosthetic treatment will be more effective if the maxillary bone tissue is reconstructed

Long term physicochemical stability study of novel ophthalmic formulations combining ceftazidime and vancomycin with and without cyclodextrins

Ceftazidime (CZ) and Vancomycin (VM) are used to treat bacterial keratitis; however, their physicochemical incompatibility does not allow their co-administration. This incompatibility can be managed by buffering the mixture at an alkaline pH or by using cage molecules such as cyclodextrins (CD). The objective of this work was to compare the stability during 168 days of frozen storage of two formulations combining VA and CZ at a final concentration of 25 mg/mL: a CD-free formulation, at a pH=8.5 and a formulation with CD

Stability of an ophthalmic formulation of polyhexamethylene biguanide in gamma-sterilized and ethylene oxide sterilized low density polyethylene multidose eyedroppers

Background Polyhexamethylene biguanide (PHMB) eye drops are a frequently used medication to treat Acanthamoeba keratitis. In the absence of marketed PHMB eye drops, pharmacy-compounding units are needed to prepare this much needed treatment, but the lack of validated PHMB stability data severely limits their conservation by imposing short expiration dates after preparation. In this study we aim to assess the physicochemical and microbiological stability of a 0.2 mg/mL PHMB eye drop formulation stored in two kinds of polyethylene bottles at two different temperatures. Methods A liquid chromatography coupled with diode array detector stability-indicating method was validated to quantify PHMB, using a cyanopropyl bonded phase (Agilent Zorbax Eclipse XDB-CN column 4.6 × 75 mm with particle size of 3.5 μm) and isocratic elution consisting of acetonitrile/deionized water (3/97 v/v) at a flow rate of 1.3 mL/min. PHMB eye drops stability was assessed for 90 days of storage at 5 and 25 °C in ethylene oxide sterilized low density polyethylene (EOS-LDPE) and gamma sterilized low density polyethylene (GS-LDPE) bottles. The following analyses were performed: visual inspection, PHMB quantification and breakdown products (BPs) screening, osmolality and pH measurements, and sterility assessment. PHMB quantification and BP screening was also performed on the drops emitted from the multidose eyedroppers to simulate in-use condition. Results The analytical method developed meets all the qualitative and quantitative criteria for validation with an acceptable accuracy and good linearity, and is stability indicating. During 90 days of storage, no significant decrease of PHMB concentration was found compared to initial concentration in all stored PHMB eye drops. However, BP were found at day 30 and at day 90 of monitoring in both kind of bottles, stored at 5 and 25 °C, respectively. Although no significant variation of osmolality was found and sterility was maintained during 90 days of monitoring, a significant decrease of pH in GS-LDPE PHMB eye drops was noticed reaching 4 and 4.6 at 25 °C and 5 °C respectively, compared to initial pH of 6.16. Discussion Although no significant decrease in PHMB concentration was found during 90 days of monitoring in all conditions, the appearance of BPs and their unknown toxicities let us believe that 0.2 mg/mL PHMB solution should be conserved for no longer than 60 days in EOS-LDPE bottles at 25 °C

Long term physicochemical stability study of novel ophthalmic formulations combining ceftazidime and vancomycin with and without cyclodextrins

International audienceAbstract Objectives Ceftazidime (CZ) and Vancomycin (VM) are used to treat bacterial keratitis; however, their physicochemical incompatibility does not allow their co-administration. This incompatibility can be managed by buffering the mixture at an alkaline pH or by using cage molecules such as cyclodextrins (CD). The objective of this work was to compare the stability during 168 days of frozen storage of two formulations combining VA and CZ at a final concentration of 25 mg/mL: a CD-free formulation, at a pH=8.5 and a formulation with CD. Methods Beforehand, a stability indicating method (SIM) was developed. Samples were analysed after 1, 3 and 6 months, and after 12, 24 and 72 h after defrosting. Analyses performed were the following: visual inspection, chromaticity, turbidity, osmolality and pH measurements, particles counting, CZ and VM quantification, breakdown product research, and sterility assay. Results The developed SIM allowed the simultaneous quantification and breakdown products research of both VM and CZ, without interference of the breakdown products. The analyses showed the presence of a visually detectable precipitate and increased turbidity as early as the first day after thawing for CD-free formulation and on the third day for the formulation with CD. CZ concentrations systematically decreased after thawing for both formulations whilst VM concentrations remained stable. Osmolality and pH remained unchanged, and no microbial growth was detected throughout the study. Conclusions CD delayed precipitation by 48 h compared to the CD-free formulation but did not permanently eliminate it. Both formulations showed very limited physicochemical stability after thawing

Evaluation of color changes during stability studies using spectrophotometric chromaticity measurements versus visual examination

International audienceAbstract Stability studies are essential to be able to assign an expiration date to medications. Color variation is one of the organoleptic characteristics of actives substances or medications which can indicate the presence of contaminations, impurities or degradations products. However there is no data available comparing the often used visual examination with spectrophotometric measurements during stability studies. The aim of this study was therefore to evaluate precisely how different the two methods are, by comparing the change of color of two drug formulations chosen as models, assessed by visual examination versus a spectrophotometric colorimetric analysis. Paracetamol and parenteral nutrition solutions were stored in stress conditions for up to 46 days, and were subjected to a visual examination using color reference solutions and to lightness and chromaticity measurement to determine their specific color by UV–Vis spectrophotometry. The color of paracetamol solutions changed faster when exposed to stress condition (light), as did the PNS when exposed to heat. In both cases, color variations were detected earlier and more precisely by UV–Vis spectrophotometry than by visual examination. Color measurement using an UV–Vis spectrophotometry should advantageously replace visual examination when assessing colors changes during drug stability studies

Stability of Ophthalmic Atropine Solutions for Child Myopia Control

International audienceMyopia is an ophthalmic condition affecting more than 1/5th of the world population, especially children. Low-dose atropine eyedrops have been shown to limit myopia evolution during treatment. However, there are currently no commercial industrial forms available and there is little data published concerning the stability of medications prepared by compounding pharmacies. The objective of this study was to evaluate the stability of two 0.1 mg/mL atropine formulations (with and without antimicrobiobial preservatives) for 6 months in two different low-density polyethylene (LDPE) multidose eyedroppers. Analyses used were the following: visual inspection, turbidity, chromaticity measurements, osmolality and pH measurements, atropine quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. In an in-use study, atropine quantification was also performed on the drops emitted from the multidose eyedroppers. All tested parameters remained stable during the 6 months period, with atropine concentrations above 94.7% of initial concentration. A breakdown product (tropic acid) did increase slowly over time but remained well below usually admitted concentrations. Atropine concentrations remained stable during the in-use study. Both formulations of 0.1 mg/mL of atropine (with and without antimicrobial preservative) were proved to be physicochemically stable for 6 months at 25 °C when stored in LDPE bottles, with an identical microbial shelf-life

Do Ophthalmic Solutions of Amphotericin B Solubilised in 2-Hydroxypropyl-γ-Cyclodextrins Possess an Extended Physicochemical Stability?

International audienceFungal keratitis is a sight-threatening disease for which amphotericin B eye drops is one of the front-line treatments. Unfortunately, there are currently no commercial forms available, and there is little data concerning the long-term stability of compounded formulations based on intravenous dosages forms. New formulations of amphotericin B ophthalmic solutions solubilised with γ-cyclodextrins have shown promising in-vitro results, but stability data is also lacking. The objective of this study was therefore to investigate the stability of a formulation of ready-to-use amphotericin B solubilised in 2-hydroxypropyl-γ-cyclodextrins (AB-HP-γ-CD), for 350 days. An amphotericin B deoxycholate (ABDC) formulation was used as a comparator. Analyses used were the following: visual inspection, turbidity, osmolality and pH measurements, amphotericin B quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. AB-HP-γ-CD formulation showed signs of chemical instability (loss of amphotericin B) after 28 and 56 days at 25 °C and 5 °C. Adding an antioxidant (ascorbic acid) to the formulation did not improve stability. ABDC formulation showed signs of physical instability (increased turbidy and amphotericin B precipitation) after 28 days and 168 days at 25 °C and 5 °C. As such, AB-HP-γ-CD formulation does not provide long-term stability for ophthalmic amphotericin B solutions

Physicochemical Stability of a Novel Tacrolimus Ophthalmic Formulation for the Treatment of Ophthalmic Inflammatory Diseases

International audienceTacrolimus is an immunosuppressant used to treat a large variety of inflammatory or immunity-mediated ophthalmic diseases. However, there are currently no commercial industrial forms available that can provide relief to patients. Various ophthalmic formulations have been reported in the literature, but their stability has only been tested over short periods. The objective of this study was to evaluate the physicochemical stability of a preservative-free tacrolimus formulation (0.2 and 1 mg/mL) at three storage temperatures (5 °C, 25 °C and 35 °C) for up to nine months in a multidose eyedropper. Analyses performed were the following: visual inspection and chromaticity, turbidity, viscosity, size of micelles, osmolality and pH measurements, tacrolimus quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. In an in-use study, tacrolimus quantification was also performed on the drops emitted from the eyedroppers. All tested parameters remained stable during the nine month period when the eyedrops were stored at 5 °C. However, during storage at 25 °C and 35 °C, several signs of chemical instability were detected. Furthermore, a leachable compound originating from a silicone part of the eyedropper was detected during the in-use assay. Overall, the 0.2 mg/mL and 1 mg/mL tacrolimus ophthalmic solutions were physicochemically stable for up to nine months when stored at 5 °C

Effects of flow rate on the migration of different plasticizers from PVC infusion medical devices.

Infusion medical devices (MDs) used in hospitals are often made of plasticized polyvinylchloride (PVC). These plasticizers may leach out into infused solutions during clinical practice, especially during risk-situations, e.g multiple infusions in Intensive Care Units and thus may enter into contact with the patients. The migrability of the plasticizers is dependent of several clinical parameters such as temperature, contact time, nature of the simulant, etc… However, no data is available about the influence of the flow rate at which drug solutions are administrated. In this study, we evaluated the impact of different flow rates on the release of the different plasticizers during an infusion procedure in order to assess if they could expose the patients to more toxic amounts of plasticizers. Migration assays with different PVC infusion sets and extension lines were performed with different flow rates that are used in clinical practice during 1h, 2h, 4h, 8h and 24h, using a lipophilic drug simulant. From a clinical point of view, the results showed that, regardless of the plasticizer, the faster the flow rate, the higher the infused volume and the higher the quantities of plasticizers released, both from infusion sets and extension lines, leading to higher patient exposure. However, physically, there was no significant difference of the migration kinetics linked to the flow rate for a same medical device, reflecting complex interactions between the PVC matrix and the simulant. The migration was especially dependent on the nature and the composition of the medical device