A Comparative Pharmacokinetic Study for Cysteamine-Containing Eye Drops as an Orphan Topical Therapy in Cystinosis.

Cystinosis is a low-prevalence lysosomal storage disease. The pathomechanism involves abnormal functioning of the cystinosine lysosomal cystine transporter (CTNS), causing intraliposomal accumulation of the amino acid cysteine disulfide, which crystallizes and deposits in several parts of the body. The most common ophthalmic complication of cystinosis is the deposition of "gold dust" cystine crystals on the cornea, which already occurs in infancy and leads to severe photosensitivity and dry eyes as it gradually progresses with age. In the specific treatment of cystinosis, preparations containing cysteamine (CYA) are used. The availability of commercialized eyedrops for the targeted treatment is scarce, and only Cystadrops® are commercially available with strong limitations. Thus, magistral CYA-containing compounded eyedrops (CYA-CED) could have a key role in patient care; however, a rationally designed comprehensive study on the commercialized and magistral products is still missing. This work aims to build up a comprehensive study about commercialized and magistral CYA eye drops, involving pharmacokinetic and physicochemical characterization (applying mucoadhesivity, rheology test, investigation of drug release, and parallel artificial membrane permeability assays), as well as ex vivo tests, well supported by statistical analysis.

Novel Approach for the Isolation and Immobilization of a Recombinant Transaminase: Applying an Advanced Nanocomposite System.

The increasing application of recombinant enzymes demands not only effective and sustainable fermentation, but also highly efficient downstream processing and further stabilization of the enzymes by immobilization. In this study, a novel approach for the isolation and immobilization of His-tagged transaminase from Chromobacterium violaceum (CvTA) has been developed. A recombinant of CvTA was simultaneously isolated and immobilized by binding on silica nanoparticles (SNPs) with metal affinity linkers and additionally within poly(lactic acid) (PLA) nanofibers. The linker length and the nature of the metal ion significantly affected the enzyme binding efficiency and biocatalytic activity of CvTA-SNPs. The formation of PLA nanofibers by electrospinning enabled rapid embedding of CvTA-SNPs biocatalysts and ensured enhanced stability and activity. The developed advanced immobilization method reduces the time required for enzyme isolation, purification and immobilization by more than fourfold compared to a classical stepwise technique.

Lipid-Based Nanocarriers for Delivery of Neuroprotective Kynurenic Acid: Preparation, Characterization, and BBB Transport.

Encapsulation possibilities of an extensively investigated neuroprotective drug (kynurenic acid, KYNA) are studied via lipid-based nanocarriers to increase the blood-brain barrier (BBB) specific permeability. The outcomes of various preparation conditions such as stirring and sonication time, concentration of the lipid carriers and the drug, and the drug-to-lipid ratio are examined. Considering the experimentally determined encapsulation efficiency, hydrodynamic diameter, and ζ-potential values, the initial lipid and drug concentration as well as the stirring and sonication time of the preparation were optimized. The average hydrodynamic diameter of the prepared asolectin-(LIP) and water-soluble lipopolymer (WSLP)-based liposomes was found to be ca. 25 and 60 nm under physiological conditions. The physicochemical characterization of the colloidal carriers proves that the preparation of the drug-loaded liposomes was a successful process, and secondary interactions were indicated between the drug molecule and the polymer residues around the WSLP membrane. Dissolution profiles of the active molecule under physiological conditions were registered, and the release of the unformulated and encapsulated drug is very similar. In addition to this outcome, the in vitro polar brain lipid extract (porcine)-based permeability test proved the achievement of two- or fourfold higher BBB specific penetration and lipid membrane retention for KYNA in the liposomal carriers relative to the unformatted drug.

Optimization and Characterization of Sodium Alginate Beads Providing Extended Release for Antidiabetic Drugs.

The current research is aimed at investigating the relationship between the formulation components and conditions in the case of a binary drug delivery system, where antidiabetic drugs are co-formulated into polymeric micelles embedded in sodium alginate. Compared to chemical modifications of polymers with alginate, our development provides a simpler and scalable formulation process. Our results prove that a multi-level factorial design-based approach can ensure the development of a value-added polymeric micelle formulation with an average micelle size of 123.6 ± 3.1 nm and a monodisperse size distribution, showing a polydispersity index value of 0.215 ± 0.021. The proper nanoparticles were co-formulated with sodium alginate as a biologically decomposing and safe-to-administer biopolymer. The Box-Behnken factorial design ensured proper design space development, where the optimal sodium alginate bead formulation had a uniform, extended-release drug release mechanism similar to commercially available tablet preparations. The main conclusion is that the rapid-burst-like drug release can be hindered via the embedment of nanocarriers into biopolymeric matrices. The thermally stable formulation also holds the benefit of uniform active substance distribution after freeze-drying.

Universal newborn hearing screening with automated auditory brainstem response (AABR) in Hungary: 5-year experience in diagnostics and influence on the early intervention.

PURPOSE: In 2015 a new regulation and guidelines for the universal newborn hearing screening by AABR measurement have been implemented in Hungary. The aim of our study was to analyse (1) the past 5 years of data from our diagnostic centre about the incidence and types of congenital hearing losses, and (2) the first experiences with the National Newborn Hearing Screening Registry, started in 2019, and (3) the influence of the screening on the pediatric cochlear implant program. METHODS: 1269 children referred to our diagnostic centre between 2017 and 2021 were investigated. A third AABR measurement and full audiological evaluation were performed. Furthermore, one-year period data of the screening registry, and the number of implanted children at or under the age of 3 were analysed using the national databases. RESULTS: Altogether 276 newborns (22% of the referred cases after the two-stage screening) had hearing loss, 134 (49%) out of them was conductive origin, almost twice frequent in male as in female. Permanent sensorineural hearing impairment was found in 142 (51%), 58 (40%) of them had bilateral, severe to profound hearing loss, occurring more frequently in male as in female. The national digital registration of the screening data within 12 months concerned 68%. The number of early cochlear implantation in one year increased from 1 to 23 children in the past 15 years. CONCLUSION: A third AABR after the two-stage screening increased the efficiency and filtered the 78% false-positive cases. The audiological diagnostics verified and typed the hearing losses ensuring the early intervention.

Pediatric morphometric study to guide the optimized implantation of the Osia® 2 implant system.

PURPOSE: Continuous technological advances result in the availability of new bone conduction hearing implants, of which their suitability for pediatric patients is of major concern. The CochlearTMOsia® 2 is a new active osseointegrated steady-state implant system that uses digital piezoelectric stimulation to treat hearing loss. The implant in the United States was approved for patients aged 12 years and above, whereas the CE mark is independent of age, the only requirement is body weight of at least 7 kg. Therefore, further clinical studies are required to assess device characteristics in younger patients. The aim of our study was to perform a morphometric study among 5-12-year-old children, and to develop a surgical protocol for Osia 2 system implantation based on these findings. METHODS: We examined retrospectively cranial CT scans of 5-12-year-old patients from our clinical database. We measured the bone and soft-tissue thickness in the region of interest, and the position of the sigmoid sinus. 3D printed temporal bones were also used for planning. RESULTS: Soft-tissue thickness varied between 3.2 ± 0.5 mm and 3.6 ± 0.6 mm and bone thickness varied between 3.5 ± 1.1 mm and 4.7 ± 0.3 mm. The sigmoid sinus was located 1.3 ± 0.2 cm posterior to the ear canal, and the anterior distance was 4.8 ± 0.9 to 7.1 ± 1.1 mm. CONCLUSIONS: Our morphometric studies showed that patients aged 5-12 have different anatomical dimensions compared to adults, but that implantation of the Osia 2 system is feasible in these patients using an altered implant positioning recommended by our data. The Cochlear™ Osia® 2 is, therefore, an option for hearing rehabilitation in younger pediatrics.

In Vitro Comparative Study of Solid Lipid and PLGA Nanoparticles Designed to Facilitate Nose-to-Brain Delivery of Insulin.

The brain insulin metabolism alteration has been addressed as a pathophysiological factor underlying Alzheimer's disease (AD). Insulin can be beneficial in AD, but its macro-polypeptide nature negatively influences the chances of reaching the brain. The intranasal (IN) administration of therapeutics in AD suggests improved brain-targeting. Solid lipid nanoparticles (SLNs) and poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) are promising carriers to deliver the IN-administered insulin to the brain due to the enhancement of the drug permeability, which can even be improved by chitosan-coating. In the present study, uncoated and chitosan-coated insulin-loaded SLNs and PLGA NPs were formulated and characterized. The obtained NPs showed desirable physicochemical properties supporting IN applicability. The in vitro investigations revealed increased mucoadhesion, nasal diffusion, and drug release rate of both insulin-loaded nanocarriers over native insulin with the superiority of chitosan-coated SLNs. Cell-line studies on human nasal epithelial and brain endothelial cells proved the safety IN applicability of nanoparticles. Insulin-loaded nanoparticles showed improved insulin permeability through the nasal mucosa, which was promoted by chitosan-coating. However, native insulin exceeded the blood-brain barrier (BBB) permeation compared with nanoparticulate formulations. Encapsulating insulin into chitosan-coated NPs can be beneficial for ensuring structural stability, enhancing nasal absorption, followed by sustained drug release.

Quality-by-Design-Based Development of n-Propyl-Gallate-Loaded Hyaluronic-Acid-Coated Liposomes for Intranasal Administration.

The present study aimed to develop n-propyl gallate (PG)-encapsulated liposomes through a novel direct pouring method using the quality-by-design (QbD) approach. A further aim was to coat liposomes with hyaluronic acid (HA) to improve the stability of the formulation in nasal mucosa. The QbD method was used for the determination of critical quality attributes in the formulation of PG-loaded liposomes coated with HA. The optimized formulation was determined by applying the Box-Behnken design to investigate the effect of composition and process variables on particle size, polydispersity index (PDI), and zeta potential. Physiochemical characterization, in vitro release, and permeability tests, as well as accelerated stability studies, were performed with the optimized liposomal formulation. The optimized formulation resulted in 90 ± 3.6% encapsulation efficiency, 167.9 ± 3.5 nm average hydrodynamic diameter, 0.129 ± 0.002 PDI, and -33.9 ± 4.5 zeta potential. Coated liposomes showed significantly improved properties in 24 h in an in vitro release test (>60%), in vitro permeability measurement (420 µg/cm2) within 60 min, and also in accelerated stability studies compared to uncoated liposomes. A hydrogen-peroxide-scavenging assay showed improved stability of PG-containing liposomes. It can be concluded that the optimization of PG-encapsulated liposomes coated with HA has great potential for targeting several brain diseases.

Synthesis and Statistical Optimization of Poly (Lactic-Co-Glycolic Acid) Nanoparticles Encapsulating GLP1 Analog Designed for Oral Delivery.

PURPOSE: To design and stabilize Liraglutide loaded poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) proper for oral administration. METHODS: PLGA NPs were prepared by means of double emulsion solvent evaporation method and optimized by applying 7-factor 2-level Plackett-Burman screening design. RESULTS: Spherical shaped NPs with homogeneous distribution, 188.95 nm particle size and 51.81% encapsulation efficiency were obtained. Liraglutide was successfully entrapped in the NPs while maintaining its native amorphous nature, and its structural integrity as well. CONCLUSION: Lira-PLGA NPs with the required Critical Quality Attributes (CQAs) were successfully designed by implementing a 7-factor 8-run Plackett Burman design into the extended Quality by Design (QbD) model, to elucidate the effect of formulation and process variables on the particle size, size-distribution, encapsulation efficiency and surface charge. As the developed nanoparticles maintained the native structure of the active pharmaceutical ingredient (API), they are promising compositions for the further development for the oral delivery of Lira. Graphical Abstract.

Novel electrocardiographic dyssynchrony criteria improve patient selection for cardiac resynchronization therapy.

Aims: We hypothesized that the greater the intra- or interventricular dyssynchrony (intraD, interD), the more effective cardiac resynchronization therapy (CRT) is. We sought to improve patient selection for CRT by using novel ECG dyssynchrony criteria. Methods and results: Left ventricular (LV) intraD was estimated by the absolute time difference between the intrinsicoid deflections (ID) in leads aVL and aVF divided by the QRS duration (QRSd): [aVLID - aVFID]/QRSd (%). InterD was estimated from the formula: [V5ID - V1ID]/QRSd (%). Their >25% value indicated electrical dyssynchrony present (ED+) and ≤25% value electrical dyssynchrony absent (ED-) diagnoses. Using the intraD + interD criteria (intra + interDC) together, if at least one of them indicated ED+ diagnosis, a final ED+ diagnosis, if both indicated ED- diagnosis, a final ED- diagnosis was made. Two authors, blinded to CRT response, retrospectively analysed pre-CRT ECGs of 124 patients with known CRT outcome. CRT response was defined as improvement of ≥ 1 NYHA class, being alive and having no hospitalizations for heart failure during 6 months of follow-up. 35/124 (28%) patients were non-responders (NRs), using the traditional criteria (TC) correct diagnosis was made in the remaining 89/124 (72%) responder (R) cases. The test accuracy (TA) of intra + interDC + TC [100/124 (81%), P < 0.001] was superior to that of TC [89/124 (72%)] due to its superior TA [36/43 (84%) vs. 29/43 (67%), respectively, P = 0.0156] in the non-specific intra-ventricular conduction disturbance (NICD) subgroup [43/124 (35%)]. In the left bundle branch block subgroup [70/124 (56%)] there was no between-criteria difference in TA. Conclusion: The intra + interDC + TC predicts clinical response after CRT more accurately than TC alone, due to greater TA in the NICD subgroup.

The Effect of an Optimized Wet Milling Technology on the Crystallinity, Morphology and Dissolution Properties of Micro- and Nanonized Meloxicam.

This article reports on the effects of a new combined wet milling technique on the physicochemical properties of meloxicam (MEL). The influence of milling time on the particle size, the crystallinity, the morphology and the dissolution rate of MEL has been studied in the presence and absence of polyvinyl alcohol (PVA) as a stabilizer agent. Micronized MEL particles were produced in aqueous medium which did not contain additive after milling for 10 min. For nanonization an additive and longer milling time were required. After particle size determination the structural and morphological characterization of the wet milled, dried products containing MEL were studied. X-ray powder diffractometry (XRPD) and differential scanning calorimetry (DSC) examinations revealed the change in the crystallinity of MEL. Scanning electron microscopy (SEM) images showed that aggregates of nanosized MEL particles were formed, regardless of the presence of PVA. The nanonized MEL crystals (D50 = 126 nm) exhibited a regular shape and a smooth surface. The increased specific surface area resulted in a high dissolution rate and concentration of free MEL. According to the results, the produced samples could be applied as a basic material (micronized MEL) and intermediate product (micronized and nanonized MEL with PVA) for the design of dosage forms.

[Postoperative monitoring of children with obstructive sleep apnea syndrome]. / Obstruktív alvási apnoe szindrómában szenvedo gyermekek posztoperatív monitorozása.

INTRODUCTION: Treatment of pediatric obstructive sleep apnea syndrome is surgical. The incidence of postoperative respiratory complications in this population is 5-25%. AIM: The aim of the authors was to present the preoperative evaluation and monitoring procedure elaborated in Heim Pál Children Hospital, Budapest. METHOD: 142 patients were involved in the study. Patient history was obtained and physical examination was performed in all cases. Thereafter, polysomnography was carried out, the severity of the obstructive sleep apnea syndrome was determined, and the patients underwent tonsilloadenotomy. RESULTS: 45 patients with mild, 50 patients with moderate and 47 patients with severe obstructive sleep apnea syndrome were diagnosed. There was no complication in patients with mild disease, while complications were observed in 6 patients in the moderate group and 24 patients in the severe group (desaturation, apnea, stridor, stop breathing) (p<0.000). In patients with severe obstructive sleep apnea syndrome, no significant difference was noted in preoperative apnoea-hypapnea index (p = 0.23) and in nadir oxygen saturation values (p = 0.73) between patients with and without complication. CONCLUSIONS: Patients with severe obstructive sleep apnea syndrome should be treated in hospital where pediatric intensive care unit is available.

[Investigation of the recrystallization of trehalose as a good glass-former excipient]. / A trehalóz, mint amorfizálódásra hajlamos segédanyag, rekrisztallizációjának vizsgálata.

An amorphous form of trehalose is easy to prepare by using a solvent method. The recrystallization kinetics can be followed well, which is important because of the occurrence of polymorphic forms of trehalose. This is especially significant in the case of dry powder inhalers. Spray-drying was used as a preparation method this being one of the most efficient technologies with which to obtain an amorphous form. This method can result in the required particle size and a monodisperse distribution with excellent flowability and with moreover considerable amorphization. In our work, trehalose was applied as a technological auxiliary agent, and literature data relating to the spray-drying technology of trehalose were collected. Studies were made of the influence of the spraying process on the amorphization of trehalose and on the recrystallization of amorphous trehalose during storage. Amorphous samples were investigated under 3 different conditions during 3 months. The recrystallization process was followed by differential scanning calorimetry and X-ray powder diffraction. The results demonstrated the perfect amorphization of trehalose during the spray-drying process. The glass transition temperature was well measurable in the samples and proved to be the same as the literature data. Recrystallization under normal conditions was very slow but at high relative humidity the process was accelerated greatly. Amorphous trehalose gave rise to dihydrate forms (gamma- and h-trehaloses) during recrystallization, and beta-trehalose was also identified as an anhydrous form.

Risperidone-Loaded Nasal Thermosensitive Polymeric Micelles: Quality by Design-Based Formulation Study.

The current research aims to develop thermosensitive polymeric micelles loaded with risperidone for nasal administration, emphasizing the added benefits of their thermosensitive behavior under nasal conditions. An initial risk assessment facilitated the advanced development process, confirming that the key indicators of thermosensitivity were suitable for nasal application. The polymeric micelles exhibited an average size of 118.4 ± 3.1 nm at ambient temperature and a size of 20.47 ± 1.2 nm at 36.5 °C, in both cases in monodisperse distribution. Factors such as pH and viscosity did not significantly impact these parameters, demonstrating appropriate nasal applicability. The model formulations showed a rapid, burst-like drug release profile in vitro, accompanied by a quick and high permeation rate at nasal conditions. Overall, the Quality by Design-based risk assessment process led to the development of an advanced drug delivery system capable of administering risperidone through the nasal cavity.

Essential considerations towards development of effective nasal antibiotic formulation: features, strategies, and future directions.

INTRODUCTION: Intranasal antibiotic products are gaining popularity as a promising method of administering antibiotics, which provide numerous benefits, e.g. enhancing drug bioavailability, reducing adverse effects, and potentially minimizing resistance threats. However, some issues related to the antibiotic substances and nasal route challenges must be addressed to prepare effective formulations. AREAS COVERED: This review focuses on the valuable points of nasal delivery as an alternative route for administering antibiotics, coupled with the challenges in the nasal cavity that might affect the formulations. Moreover, this review also highlights the application of nasal delivery to introduce antibiotics for local therapy, brain targeting, and systemic effects that have been conducted. In addition, this viewpoint provides strategies to maintain antibiotic stability and several crucial aspects to be considered for enabling effective nasal formulation. EXPERT OPINION: In-depth knowledge and understanding regarding various key considerations with respect to the antibiotic substances and nasal route delivery requirement in preparing effective nasal antibiotic formulation would greatly improve the development of nasally administered antibiotic products, enabling better therapeutic outcomes of antibiotic treatment and establishing appropriate use of antibiotics, which in turn might reduce the chance of antibiotic resistance and enhance patient comfort.

Novel electrocardiographic criteria may render possible the more accurate recognition of cardiac amyloidosis.

AIMS: The early diagnosis of cardiac amyloidosis (CA) is paramount, since there are effective therapies that improve patient survival. The diagnostic accuracy of classical electrocardiographic (ECG) signs, such as low voltage, pseudoinfarct pattern, and conduction disturbances in the diagnosis of CA, is inferior to that of the echocardiographic myocardial deformation criteria; therefore, our aim was to find more accurate novel ECG criteria for this purpose. METHODS: We tested the diagnostic value of five novel ECG criteria, two of them devised by us, in 34 patients with confirmed CA (20 transthyretin amyloidosis and 14 AL amyloidosis) and 45 control patients with left ventricular hypertrophy on echocardiography due to hypertension, valvular aortic stenosis and hypertrophic cardiomyopathy. The following novel ECG criteria, that suggested CA, were tested: QRS amplitude in lead I < 0.55 mV (I < 0.55); QRS amplitude in lead aVR < 0.5 mV (aVR < 0.5); average QRS amplitude of leads I + aVR < 0.575 mV [(I + aVR) < 0.575]; average QRS amplitude of leads I + aVR/average QRS amplitude of leads V1-4 < 0.375 [(I + aVR)/(V1-4) < 0.375]; average QRS amplitude of leads I + aVR/longest intrinsicoid deflection in leads I,aVL,V1-6 < 0.0115 [(I + aVR)/I,aVL,V1-6ID < 0.0115]. RESULTS: The I < 0.55, aVR < 0.5, (I + aVR) < 0.575, (I + aVR)/(V1-4) < 0.375, (I + aVR)/I,aVL,V1-6ID < 0.0115 test accuracy (TA) were 81%, 84.8%, 82.3%, 84.8%, and 83.3%, respectively; the sensitivity (SE): 76.5%, 82.4%, 85.3%, 82.4%, and 76.9%; specificity (SP): 84.4%, 86.7%, 80%, 86.7%, and 87.5%; positive predictive values (PPV): 78.8%, 82.4%, 76.3%, 82.4%, and 80%; negative predictive values (NPV): 82.6%, 86.7%, 87.8%, 86.7%, and 85.4%; area under curve (AUC) values: 0.8922, 0.8794, 09016, 0.8824, and 0.8462 were respectively. These parameters of the novel ECG criteria were at least as good as those reported by other authors in the literature of the qualitative (TA: 67%, SE: 80%, SP: 34%, PPV: 75%, NPV: 42%, AUC: 0.57) and quantitative apical sparing (TA: 64-80%, SE: 66-81.3%, SP: 55-78.3%, PPV: 33-83.9%, NPV: 41-75%, AUC: 0.62-0.68) and left ventricular ejection fraction/global longitudinal strain >4.1 (TA: 77%, SE: 93%, SP: 38%, PPV: 79%, NPV: 69%, AUC: 0.65) echocardiographic criteria. Among the classical criteria, the low voltage in limb leads criterion was present most frequently (in 73.5%) in patients with CA, with slightly worse diagnostic value than the novel ECG criteria (TA: 78.5%, SE: 73.5%, SP: 82.2%, PPV: 75.8%, NPV: 80.4%). CONCLUSIONS: The novel ECG criteria [mostly the aVR < 0.5, (I + aVR)/(V1-4) < 0.375] seem at least as reliable in the diagnosis of CA as the best echocardiographic myocardial deformation criteria and might be used either together with the echocardiographic criteria or as stand-alone criteria to diagnose CA in the future.

Immobilization of human tyrosine hydroxylase onto magnetic nanoparticles - A novel formulation of a therapeutic enzyme.

Human tyrosine hydroxylase (hTH) has key role in the production of catecholamine neurotransmitters. The structure, function and regulation of hTH has been extensively researched area and the possibility of enzyme replacement therapy (ERT) involving hTH through nanocarriers has been raised as well. However, our understanding on how hTH may interact with nanocarriers is still lacking. In this work, we attempted to investigate the immobilization of hTH on magnetic nanoparticles (MNPs) with various surface linkers in quantitative and mechanistic detail. Our results showed that the activity of hTH was retained after immobilization via secondary and covalent interactions as well. The colloidal stability of hTH could be also enhanced proved by Dynamic light scattering and Zeta potential analysis and a homogenous enzyme layer could be achieved, which was investigated by Raman mapping. The covalent attachment of hTH on MNPs via aldehyde or epoxy linkers provide irreversible immobilization and 38.1 % and 16.5 % recovery (ER). The hTH-MNPs catalyst had 25 % ER in average in simulated nasal electrolyte solution (SNES). This outcome highlights the relevance of immobilization applying MNPs as a potential formulation tool of sensitive therapeutic enzymes offering new opportunities for ERT related to neurodegenerative disorders.

Exploring Vacuum Compression Molding as a Preparation Method for Flexible-Dose Pediatric Orodispersible Films.

In recent years, solid dosage forms have gained interest in pediatric therapy because they can provide valuable benefits in terms of dose accuracy and stability. Particularly for orodispersible films (ODFs), the literature evidences increased acceptability and dose flexibility. Among the various available technologies for obtaining ODFs, such as solvent casting, hot-melt extrusion, and ink printing technologies, the solvent-free preparation methods exhibit significant advantages. This study investigated Vacuum Compression Molding (VCM) as a solvent-free manufacturing method for the preparation of flexible-dose pediatric orodispersible films. The experimental approach focused on selecting the appropriate plasticizer and ratios of the active pharmaceutical ingredient, diclofenac sodium, followed by the study of their impacts on the mechanical properties, disintegration time, and drug release profile of the ODFs. Additional investigations were performed to obtain insights regarding the solid-state properties. The ODFs obtained by VCM displayed adequate quality in terms of their critical characteristics. Therefore, this proof-of-concept study shows how VCM could be utilized as a standalone method for the production of small-scale ODFs, enabling the customization of doses to meet the individual needs of pediatric patients.

Timely recanalization of lateral sinus thrombosis in children: should we consider hypoplasia of contralateral sinuses in treatment planning?

The objective of this study was to evaluate long-term clinical and radiological outcomes in children treated with lateral sinus thrombosis secondary to acute mastoiditis considering also contralateral sinus hypoplasia. This study was a retrospective chart review, conducted in tertiary pediatric hospital. Medical reports of eight children with acute mastoiditis and lateral sinus thrombosis from 1998 to 2011 were examined in terms of therapy, clinical recovery and radiological proof of lateral sinus recanalization. Three children presented hypoplasia of contralateral venous drainage system. Condition of sinuses was regularly monitored with MRI. Otologically and neurologically, all children recovered fully. All received antibiotics; six received additional low molecular weight heparin therapy. Mastoidectomy was performed on six cases. Incision and thrombectomy were applied in the other two, one involving internal jugular vein ligation. This latter case presented also contralateral venous hypoplasia; visual impairment proved permanent. The other two children with contralateral sinus hypoplasia recovered fully after steroid, dehydration and low molecular weight heparin therapy. Recanalization occurred in all children except the one with internal jugular vein ligation, in whom good collateral circulation was observed. There were no bleeding complications. Anatomical variations of cerebral venous drainage system can frequently be observed and should be considered in treatment planning. Mastoidectomy with antibiotics and additional low molecular weight heparin treatment is a safe, promising alternative to thrombectomy and internal jugular vein ligation in children with lateral sinus thrombosis following acute mastoiditis, also having contralateral sinus hypoplasia. Recanalization can be expected within two to five months.