3D-printed prednisolone phosphate suppositories with tunable dose and rapid release for the treatment of inflammatory bowel disease.

Established medicines are often not tailored to the needs of the pediatric population, causing difficulties with administration or dosing. Three-dimensional (3D) printing technology allows novel approaches for compounding of personalized medicine, as is exemplified in this study for the automated compounding of rectal preparations for children. We investigated the material requirements to print prednisolone phosphate-loaded suppositories with tunable dose and rapid drug release for the treatment of inflammatory bowel diseases. Three formulations containing 4 % w/w prednisolone sodium phosphate (PSP) and different amounts of hydroxypropyl cellulose (HPC) and mannitol as excipients were printed as suppositories with a fused deposition modeling (FDM) 3D-printer. Dissolution studies showed that the PSP release rate was increased when higher weight fractions of mannitol were added as a pore former, with 90 % drug release within 30 min for mannitol 48 % w/w. We further printed suppositories with 48 % mannitol with different infill densities and dimensions to tune the dose. Our findings demonstrated that 3D-printed suppositories with PSP doses ranging from 6 to 30 mg could be compounded without notably affecting the dissolution kinetics, ensuring equivalent therapeutic efficacies for different doses.

Effects of enzyme replacement therapy on cardiac function in classic infantile Pompe disease.

OBJECTIVE: Patients with classic infantile Pompe disease are born with a hypertrophic cardiomyopathy, which resolves after treatment with Enzyme replacement therapy (ERT). We aimed to assess potential deterioration of cardiac function over time using myocardial deformation analysis. METHODS: Twenty-seven patients treated with ERT were included. Cardiac function was assessed at regular time intervals (before and after start with ERT) using conventional echocardiography and myocardial deformation analysis. Separate linear mixed effect models were used to asses temporal changes within the first year and the long-term follow-up period. Echocardiograms of 103 healthy children served as controls. RESULTS: A total of 192 echocardiograms were analyzed. Median follow-up was 9.9 years (IQR: 7.5-16.3). Mean LVMI before start of ERT was increased 292.3 g/m2 (95% CI: 202.8-381.8, mean Z-score + 7.6) and normalized after 1 year of ERT 87.3 g/m2 (CI: 67.5-107.1, mean Z-score + 0.8, p < 0.001). Mean shortening fraction was within normal limits before start of ERT, up to 22 years of follow-up. Cardiac function measured by RV/LV longitudinal, and circumferential strain was diminished before start of ERT, but normalized (<-16%) within 1 year after start of ERT, and all remained within normal limits during follow-up. Only LV circumferential strain gradually worsened in Pompe patients (+0.24%/year) during follow-up compared to controls. LV longitudinal strain was diminished in Pompe patients, but did not change significantly over time compared to controls. CONCLUSION: Cardiac function, measured using myocardial deformation analysis, normalizes after start of ERT, and seems to remain stable over a median follow-up period of 9.9 years.

Risk of Four Geriatric Syndromes: A Comparison of Mental Health Care and General Hospital Inpatients.

An observational, cross-sectional study is conducted to compare elevated risk scores of four geriatric syndromes (falls, malnutrition, physical impairment, delirium) in older hospitalized psychiatric patients (n=178) with patients hospitalized in a general hospital (n=687). The median age of all patients was 78 years (IQR 73.3-83.3), 53% were female. After correction for age and gender, we found significantly more often an elevated risk in the mental health care group, compared to the general hospital group of falls (Odds Ratio (OR) = 1.75; 95% Confidence Interval (CI) 1.18-2.57), malnutrition (OR = 4.12; 95% CI 2.67-6.36) and delirium (OR = 6.45; 95% CI 4.23-9.85). The risk on physical impairment was not statistically significantly different in both groups (OR = 1.36; 95% CI .90-2.07). Older mental health care patients have a higher risk to develop geriatric syndromes compared to general hospital patients with the same age and gender, which might be explained by a higher level of frailty.

Complexity and interplay of faced adversities and perceived health and well-being in highly vulnerable pregnant women-the Mothers of Rotterdam program.

BACKGROUND: Living in socially disadvantaged circumstances has a widespread impact on one's physical and mental health. That is why individuals living in this situation are often considered vulnerable. When pregnant, not only the woman's health is affected, but also that of her (unborn) child. It is well accepted that vulnerable populations experience worse (perinatal) health, however, little is known about the lived adversities and health of these vulnerable individuals. OBJECTIVES: With this article, insights into this group of highly vulnerable pregnant women are provided by describing the adversities these women face and their experienced well-being. METHODS: Highly vulnerable women were recruited when referred to tailored social care during pregnancy. Being highly vulnerable was defined as facing at least three different adversities divided over two or more life-domains. The heat map method was used to assess the interplay between adversities from the different life domains. Demographics and results from the baseline questionnaires on self-sufficiency and perceived health and well-being were presented. RESULTS: Nine hundred nineteen pregnant women were referred to social care (2016-2020). Overall, women had a median of six adversities, distributed over four life-domains. The heat map revealed a large variety in lived adversities, which originated from two parental clusters, one dominated by financial adversities and the other by a the combination of a broad range of adversities. The perceived health was moderate, and 25-34% experienced moderate to severe levels of depression, anxiety or stress. This did not differ between the two parental clusters. CONCLUSIONS: This study shows that highly vulnerable pregnant women deal with multiple adversities affecting not only their social and economic position but also their health and well-being.

[Psychiatric symptoms and COVID-19: results of a national case register]. / Psychiatrische symptomen en COVID-19: resultaten uit een landelijk register.

BACKGROUND: Psychiatric disorders are associated with a more severe course of COVID-19. COVID-19 can also lead to psychiatric symptoms. AIM: To gain insight into vulnerabilities and protective factors for the course of COVID-19 in a Dutch (neuro)psychiatric population. METHOD: Patients were divided into three groups: patients with pre-existent mental disorders without and with new (neuro)psychiatric symptoms (NPS) during COVID-19 and patients without pre-existent mental disorders who developed de novo NPS during COVID-19. We summarize the characteristics of each group and compare the subgroups with inferential statistics. RESULTS: 186 patients were included in the case register. Patients with NPS showed a more severe course of COVID-19. Mortality in patients with NPS was higher in patients with pre-existent mental disorders compared to patients without pre-existent mental disorders. The most frequently reported de novo psychiatric symptoms during COVID-19 were delirium (46-70%), anxiety (53-54%) and insomnia (18-42%). CONCLUSION: NPS might be an expression of a more severe COVID-19 episode. In patients who developed NPS during COVID-19 we found evidence for a higher mortality risk in patients with pre-existent mental disorders. Extra vigilance for neuropsychiatric symptoms during COVID-19 is warranted.

The Dutch Multidisciplinary Occupational Health Guideline to Enhance Work Participation Among Low Back Pain and Lumbosacral Radicular Syndrome Patients.

Purpose Based on current scientific evidence and best practice, the first Dutch multidisciplinary practice guideline for occupational health professionals was developed to stimulate prevention and enhance work participation in patients with low back pain (LBP) and lumbosacral radicular syndrome (LRS). Methods A multidisciplinary working group with health care professionals, a patient representative and researchers developed the recommendations after systematic review of evidence about (1) Risk factors, (2) Prevention, (3) Prognostic factors and (4) Interventions. Certainty of the evidence was rated with GRADE and the Evidence to Decision (EtD) framework was used to formulate recommendations. High or moderate certainty resulted in a recommendation "to advise", low to very low in a recommendation "to consider", unless other factors in the framework decided differently. Results An inventory of risk factors should be considered and an assessment of prognostic factors is advised. For prevention, physical exercises and education are advised, besides application of the evidence-based practical guidelines "lifting" and "whole body vibration". The stepped-care approach to enhance work participation starts with the advice to stay active, facilitated by informing the worker, reducing workload, an action plan and a time-contingent increase of work participation for a defined amount of hours and tasks. If work participation has not improved within 6 weeks, additional treatments should be considered based on the present risk and prognostic factors: (1) physiotherapy or exercise therapy; (2) an intensive workplace-oriented program; or (3) cognitive behavioural therapy. After 12 weeks, multi-disciplinary (occupational) rehabilitation therapy need to be considered. Conclusions Based on systematic reviews and expert consensus, the good practice recommendations in this guideline focus on enhancing work participation among workers with LBP and LRS using a stepped-care approach to complement existing guidelines focusing on recovery and daily functioning.

Automatic upper airway segmentation in static and dynamic MRI via anatomy-guided convolutional neural networks.

PURPOSE: Upper airway segmentation on MR images is a prerequisite step for quantitatively studying the anatomical structure and function of the upper airway and surrounding tissues. However, the complex variability of intensity and shape of anatomical structures and different modes of image acquisition commonly used in this application makes automatic upper airway segmentation challenging. In this paper, we develop and test a comprehensive deep learning-based segmentation system for use on MR images to address this problem. MATERIALS AND METHODS: In our study, both static and dynamic MRI data sets are utilized, including 58 axial static 3D MRI studies, 22 mid-retropalatal dynamic 2D MRI studies, 21 mid-retroglossal dynamic 2D MRI studies, 36 mid-sagittal dynamic 2D MRI studies, and 23 isotropic dynamic 3D MRI studies, involving a total of 160 subjects and over 20 000 MRI slices. Samples of static and 2D dynamic MRI data sets were randomly divided into training, validation, and test sets by an approximate ratio of 5:2:3. Considering that the variability of annotation data among 3D dynamic MRIs was greater than for other MRI data sets, we increased the ratio of training data for these data to improve the robustness of the model. We designed a unified framework consisting of the following procedures. For static MRI, a generalized region-of-interest (GROI) strategy is applied to localize the partitions of nasal cavity and other portions of upper airway in axial data sets as two separate subobjects. Subsequently, the two subobjects are segmented by two separate 2D U-Nets. The two segmentation results are combined as the whole upper airway structure. The GROI strategy is also applied to other MRI modes. To minimize false-positive and false-negative rates in the segmentation results, we employed a novel loss function based explicitly on these rates to train the segmentation networks. An inter-reader study is conducted to test the performance of our system in comparison to human variability in ground truth (GT) segmentation of these challenging structures. RESULTS: The proposed approach yielded mean Dice coefficients of 0.84±0.03, 0.89±0.13, 0.84±0.07, and 0.86±0.05 for static 3D MRI, mid-retropalatal/mid-retroglossal 2D dynamic MRI, mid-sagittal 2D dynamic MRI, and isotropic dynamic 3D MRI, respectively. The quantitative results show excellent agreement with manual delineation results. The inter-reader study results demonstrate that the segmentation performance of our approach is statistically indistinguishable from manual segmentations considering the inter-reader variability in GT. CONCLUSIONS: The proposed method can be utilized for routine upper airway segmentation from static and dynamic MR images with high accuracy and efficiency. The proposed approach has the potential to be employed in other dynamic MRI-related applications, such as lung or heart segmentation.

ECT non-remitters: prognosis and treatment after 12 unilateral electroconvulsive therapy sessions for major depression.

BACKGROUND: Depressive disorder causes significant suffering in patients and caregivers worldwide. Electroconvulsive therapy (ECT) is a highly effective antidepressant treatment, but little is known about the prognosis and treatment of patients who do not achieve remission with ECT. We investigated prognosis and treatment of patients with major depression who did not achieve remission after 12 unilateral electroconvulsive therapy sessions. METHODS: We conducted a retrospective, naturalistic follow-up study. Patients who had previously participated in a double-blind randomized controlled trial that compared brief pulse with ultra-brief pulse ECT and who had not achieved remission after 12 right unilateral (RUL) ECT sessions were selected for this study. We analysed the type of treatments received during the 6-month follow-up and studied the occurrence of remission and response. The primary outcome was remission, defined as a Montgomery-Åsberg Depression Rating Scale score <10. RESULTS: Eighty-one patients were randomized, of which 18 patients did not remit. Eight of these non-remitters achieved remission during follow-up (44.4%) while 7 did not achieve remission (38.9%). Remission data could not be retrieved for 3 patients (16.7%). Remission was achieved in 6 patients by a combination of continuing unilateral ECT with antidepressants or switching to bilateral ECT. LIMITATIONS: This is a retrospective study with only a small number of patients. Treatment after RUL ECT non-remission was not standardized. CONCLUSION: When patients with major depression do not achieve remission after 12 RUL ECT sessions, they have still a reasonable chance of remission within 6 months. Continuing ECT has the best chance of success.

White zein colloidal particles: synthesis and characterization of their optical properties on the single particle level and in concentrated suspensions.

Growing interest in using natural, biodegradable ingredients for food products leads to an increase in research for alternative sources of functional ingredients. One alternative is zein, a water-insoluble protein from corn. Here, a method to investigate the optical properties of white zein colloidal particles is presented in both diluted and concentrated suspensions. The particles are synthesized, after purification of zein, by anti-solvent precipitation. Mean particle diameters ranged from 35 to 135 nm based on dynamic light scattering. The value of these particles as white colorant is examined by measuring their optical properties. Dilute suspensions are prepared to measure the extinction cross section of individual particles and this was combined with Mie theory to determine a refractive index (RI) of 1.49 ± 0.01 for zein particles dispersed in water. This value is used to further model the optical properties of concentrated suspensions. To obtain full opacity of the suspension, comparable to 0.1-0.2 wt% suspensions of TiO2, concentrations of 2 to 3.3 wt% of zein particles are sufficient. The optimal size for maximal scattering efficiency is explored by modeling dilute and concentrated samples with RI's matching those of zein and TiO2 particles in water. The transport mean free path of light was determined experimentally and theoretically and the agreement between the transport mean free path calculated from the model and the measured value is better than 30%. Such particles have the potential to be an all-natural edible alternative for TiO2 as white colorant in wet food products.

Quantitative analysis of receptor-mediated uptake and pro-apoptotic activity of mistletoe lectin-1 by high content imaging.

Ribosome inactivating proteins (RIPs) are highly potent cytotoxins that have potential as anticancer therapeutics. Mistletoe lectin 1 (ML1) is a heterodimeric cytotoxic protein isolated from European Mistletoe and belongs to RIP class II. The aim of this project was to systematically study ML1 cell binding, endocytosis pathway(s), subcellular processing and apoptosis activation. For this purpose, state of the art cell imaging equipment and automated image analysis algorithms were used. ML1 displayed very fast binding to sugar residues on the membrane and energy-dependent uptake in CT26 cells. The co-staining with specific antibodies and uptake blocking experiments revealed involvement of both clathrin-dependent and -independent pathways in ML1 endocytosis. Co-localization studies demonstrated the toxin transport from early endocytic vesicles to Golgi network; a retrograde road to the endoplasmic reticulum. The pro-apoptotic and antiproliferative activity of ML1 were shown in time lapse movies and subsequently quantified. ML1 cytotoxicity was less affected in multidrug resistant tumor cell line 4T1 in contrast to commonly used chemotherapeutic drug (ML1 resistance index 6.9 vs 13.4 for doxorubicin; IC50: ML1 1.4 ng/ml vs doxorubicin 24000 ng/ml). This opens new opportunities for the use of ML1 as an alternative treatment in multidrug resistant cancers.

[ResPECT - a decade of Flemish-Dutch ECT research]. / ResPECT ­ een decennium Vlaams-Nederlands onderzoek naar elektroconvulsietherapie.

BACKGROUND: There is increasing clinical and scientific interest in electroconvulsive therapy (ECT). AIM: To provide an overview of the main research findings of the Flemish-Dutch research consortium ResPECT. METHOD: We report on our review of the relevant literature. RESULTS: Our studies confirm that ECT is one of the most efficient treatments for depression in later life and for depression with psychotic features. Older people with age-related brain pathology can respond well to ECT. It is still preferable to apply a standard pulse-width because this increases the efficacy of the treatment and minimises the cognitive impact. Even vulnerable older people can react favourably to ECT. CONCLUSION: Recent findings of the ResPECT consortium are providing new insights that are applicable in daily clinical practice. Research into mechanisms of action can also increase our understanding of the pathophysiology of severe depression.

Screening of Autism Spectrum Disorders in Geriatric Psychiatry.

Autism spectrum disorders (ASD) are difficult to detect in old age. This study examined if ASD symptoms in older adults (age > 60) can be detected with the Dutch informant personality questionnaire, (Hetero-Anamnestische Persoonlijkheidsvragenlijst, HAP) in a mental health setting. Patients with ASD (N = 40) were compared to patients with a different psychiatric diagnosis (N = 43; personality disorders excluded). The ASD group had significant higher scores on the scales 'Socially avoidant behavior', 'Rigid behavior' and 'Unpredictable and impulsive behavior'. These scales were able to discriminate between individuals with or without ASD. The HAP can thus be used as a screening instrument for ASD symptoms in elderly patients. Further research is needed to clarify what items have the best predictive validity for ASD symptoms.

Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis.

CCN-2 (connective tissue growth factor; CTGF) is a key factor in fibrosis. Plasma CCN-2 has biomarker potential in numerous fibrotic disorders, but it is unknown which pathophysiological factors determine plasma CCN-2 levels. The proteolytic amino-terminal fragment of CCN-2 is primarily eliminated by the kidney. Here, we investigated elimination and distribution profiles of full length CCN-2 by intravenous administration of recombinant CCN-2 to rodents. After bolus injection in mice, we observed a large initial distribution volume (454 mL/kg) and a fast initial clearance (120 mL/kg/min). Immunosorbent assay and immunostaining showed that CCN-2 distributed mainly to the liver and was taken up by hepatocytes. Steady state clearance in rats, determined by continuous infusion of CCN-2, was fast (45 mL/kg/min). Renal CCN-2 clearance, determined by arterial and renal vein sampling, accounted for only 12 % of total clearance. Co-infusion of CCN-2 with receptor-associated protein (RAP), an antagonist of LDL-receptor family proteins, showed that RAP prolonged CCN-2 half-life and completely prevented CCN-2 internalization by hepatocytes. This suggests that hepatic uptake of CCN-2 is mediated by a RAP-sensitive mechanism most likely involving LRP1, a member of the LDL-receptor family involved in hepatic clearance of various plasma proteins. Surface plasmon resonance binding studies confirmed that CCN-2 is an LRP1 ligand. Co-infusion of CCN-2 with an excess of the heparan sulphate-binding protamine lowered the large initial distribution volume of CCN-2 by 88 % and reduced interstitial staining of CCN-2, suggesting binding of CCN-2 to heparan sulphate proteoglycans (HSPGs). Protamine did not affect clearance rate, indicating that RAP-sensitive clearance of CCN-2 is HSPG independent. In conclusion, unlike its amino-terminal fragment which is cleared by the kidney, full length CCN-2 is primarily eliminated by the liver via a fast RAP-sensitive, probably LRP1-dependent pathway.

Relation between CYP2D6 Genotype, Phenotype and Therapeutic Drug Concentrations among Nortriptyline and Venlafaxine Users in Old Age Psychiatry.

Objectives: To determine relations between drug concentrations and the cytochrome P450-CYP2D6 genotype or phenotype among elderly patients treated with nortriptyline or venlafaxine. Methods: A post-hoc analysis of a clinical trial was performed. Patients were grouped into phenotypes according to the metabolite/mother compound ratio. Genotypes were assessed by the CYP2D6 *3 and *4 alleles. Results: Data was available from 81 patients (41 nortriptyline, 40 venlafaxine) with a mean age of 72 years. No phenoconversion from poor metabolizers (PM) to extensive metabolizers (EM), or vice versa, was found. However, we did find phenoconversion from PM to intermediate metabolizers (IM), IM to EM, or vice versa in 36% of observations. Among nortriptyline users, patients with a PM or IM genotype had more supra-therapeutic blood levels, although this did not reach statistical significance. In exploratory analyses we found men were more likely (RR: 2.4; 95% CI: 1.14-5.07) to display phenoconversion from an IM genotype to EM phenotype. In addition, compared to non-PMs, PMs were found to have higher risk (RR: 1.56; 95% CI: 1.03-2.37) on non-response, although this was only significant when response was measured on the Hamilton Rating Scale for Depression and not on the Montgomery Åsberg Depression Rating Scale. Conclusion: Patients phenoconversed, but we did not observe phenoconversion from PM to EM or vice versa. Genotype information could be used as a valuable tool, in addition to therapeutic drug monitoring, to prevent supratherapeutic drug levels of nortriptyline or venlafaxine in elderly patients with a PM genotype.

Effectiveness study of atropine for progressive myopia in Europeans.

PurposeRandomized controlled trials have shown the efficacy of atropine for progressive myopia, and this treatment has become the preferred pattern for this condition in Taiwan. This study explores the effectiveness of atropine 0.5% treatment for progressive high myopia and adherence to therapy in a non-Asian country.MethodsAn effectiveness study was performed in Rotterdam, the Netherlands. Overall 77 children (mean age 10.3 years±2.3), of European (n=53), Asian (n=18), and African (n=6) descent with progressive myopia were prescribed atropine 0.5% eye drops daily. Both parents and children filled in a questionnaire regarding adverse events and adherence to therapy. A standardized eye examination including cycloplegic refraction and axial length was performed at baseline and 1, 4, and 12 months after initiation of therapy.ResultsMean spherical equivalent at baseline was -6.6D (±3.3). The majority (60/77, 78%) of children adhered to atropine treatment for 12 months; 11 of the 17 children who discontinued therapy did so within 1 month after the start of therapy. The most prominent reported adverse events were photophobia (72%), followed by reading problems (38%), and headaches (22%). The progression rate of spherical equivalent before treatment (-1.0D/year±0.7) diminished substantially during treatment (-0.1D/year±0.7) compared to those who ceased therapy (-0.5D/year±0.6; P=0.03).ConclusionsDespite the relatively high occurrence of adverse events, our study shows that atropine can be an effective and sustainable treatment for progressive high myopia in Europeans.

Prevalence of mild cognitive impairment and dementia in older non-western immigrants in the Netherlands: a cross-sectional study.

OBJECTIVE: In the Netherlands, persons of Turkish, Moroccan and Surinamese descent form the largest groups of non-western immigrants. A high prevalence of mild cognitive impairment (MCI) and dementia has been described in immigrant populations in the United States of America and the United Kingdom. We determined the prevalence of MCI and dementia in older community-dwelling adults from the largest non-western immigrant groups in the Netherlands. METHODS: Participants, aged 55 years and older, of Turkish, Moroccan (Arabic or Berber), Surinamese (Creole or Hindustani) or Dutch descent were recruited via their general practitioners. Cognitive deficits were assessed using the Cross-Cultural Dementia screening instrument, which was validated in poorly educated people from different cultures. Differences in prevalence rates of MCI and dementia between the immigrant groups and a native Dutch group were analysed using chi-square tests. RESULTS: We included 2254 participants. Their mean age was 65.0 years (standard deviation, 7.5), and 44.4% were male. The prevalence of MCI was 13.0% in Turkish, 10.1% in Moroccan-Arabic, 9.4% in Moroccan-Berber and 11.9% in Surinamese-Hindustani participants, compared to 5.9% in Surinamese-Creoles and 3.3% in native Dutch. The prevalence of dementia was 14.8% in Turkish, 12.2% in Moroccan Arabic, 11.3% in Moroccan Berber and 12.6% in Surinamese-Hindustani participants, compared to 4.0% in Surinamese-Creoles and 3.5% in native Dutch. CONCLUSIONS: MCI and dementia were three to four times more prevalent in the majority of non-western immigrant groups when compared to the native Dutch population. These differences are important for planning and improving healthcare facilities. Copyright © 2016 John Wiley & Sons, Ltd.

Release and pharmacokinetics of near-infrared labeled albumin from monodisperse poly(d,l-lactic-co-hydroxymethyl glycolic acid) microspheres after subcapsular renal injection.

Subcapsular renal injection is a novel administration method for local delivery of therapeutics for the treatment of kidney related diseases. The aim of this study was to investigate the feasibility of polymeric microspheres for sustained release of protein therapeutics in the kidney and study the subsequent redistribution of the released protein. For this purpose, monodisperse poly(d,l-lactic-co-hydroxymethyl glycolic acid) (PLHMGA) microspheres (40 µm in diameter) loaded with near-infrared dye-labeled bovine serum albumin (NIR-BSA) were prepared by a membrane emulsification method. Rats were injected with either free NIR-BSA or with NIR-BSA loaded microspheres (NIR-BSA-ms) and the pharmacokinetics of the released NIR-BSA was studied for 3 weeks by ex vivo imaging of organs and blood. Quantitative release data were obtained from kidney homogenates and possible metabolism of the protein was investigated by SDS-PAGE analysis of the samples. The ex vivo images showed a rapid decrease of the NIR signal within 24h in kidneys injected with free NIR-BSA, while, importantly, the signal of the labeled protein was still visible at day 21 in kidneys injected with NIR-BSA-ms. SDS-PAGE analysis of the kidney homogenates showed that intact NIR-BSA was released from the microspheres. The locally released NIR-BSA drained to the systemic circulation and subsequently accumulated in the liver, where it was degraded and excreted renally. The in vivo release of NIR-BSA was calculated after extracting the protein from the remaining microspheres in kidney homogenates. The in vivo release rate was faster (89 ± 4% of the loading in 2 weeks) compared to the in vitro release of NIR-BSA (38 ± 1% in 2 weeks). In conclusion, PLHMGA microspheres injected under the kidney capsule provide a local depot from which a formulated protein is released over a prolonged time-period.

Formulation and characterization of microspheres loaded with imatinib for sustained delivery.

The aim of this study was the development of imatinib-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with high loading efficiency which can afford continuous release of imatinib over a prolonged period of time. Imatinib mesylate loaded PLGA microspheres with a size of 6-20 µm were prepared by a double emulsion (W1/O/W2) method using dichloromethane as volatile solvent. It was found that the microspheres were spherical with a non-porous surface; imatinib loading efficiency (LE) was highly dependent on the pH of the external water phase (W2). By increasing the pH of W2 phase above the highest pKa of imatinib (pKa 8.1), at which imatinib is mainly uncharged, the LE increased from 10% to 90% (pH 5.0 versus pH 9.0). Conversely, only 4% of its counter ion, mesylate, was retained in the microspheres at the same condition (pH 9.0). Since mesylate is highly water soluble, it is unlikely that it partitions into the organic phase. We demonstrated, using differential scanning calorimetry (DSC), that imatinib was molecularly dispersed in the polymeric matrix at loadings up to 8.0%. At higher drug loading, imatinib partially crystallized in the matrix. Imatinib microspheres released their cargo during three months by a combination of diffusion through the polymer matrix and polymer erosion. In conclusion, we have formulated imatinib microspheres with high LE and LC. Although we started with a double emulsion of imatinib mesylate, the obtained microspheres contained imatinib base which was mainly molecularly dispersed in the polymer matrix. These microspheres release imatinib over a 3-month period which is of interest for local treatment of cancer.

Sunitinib microspheres based on [PDLLA-PEG-PDLLA]-b-PLLA multi-block copolymers for ocular drug delivery.

Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that blocks several angiogenesis related pathways. The aim of this study was to develop sunitinib-loaded polymeric microspheres that can be used as intravitreal formulation for the treatment of ocular diseases. A series of novel multi-block copolymers composed of amorphous blocks of poly-(D,L-lactide) (PDLLA) and polyethylene glycol (PEG) and of semi-crystalline poly-(L-lactide) (PLLA) blocks were synthesized. Sunitinib-loaded microspheres were prepared by a single emulsion method using dichloromethane as volatile solvent and DMSO as co-solvent. SEM images showed that the prepared microspheres (∼ 30 µm) were spherical with a non-porous surface. Sunitinib-loaded microspheres were studied for their degradation and in-vitro release behavior. It was found that increasing the percentage of amorphous soft blocks from 10% to 30% accelerated the degradation of the multi-block copolymers. Sunitinib microspheres released their cargo for a period of at least 210 days by a combination of diffusion and polymer erosion. The initial burst (release in 24h) and release rate could be tailored by controlling the PEG-content of the multi-block copolymers. Sunitinib-loaded microspheres suppressed angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These microspheres therefore hold promise for long-term suppression of ocular neovascularization.

Depression in later life: a more somatic presentation?

BACKGROUND: Depression later in life may have a more somatic presentation compared with depression earlier in life due to chronic somatic disease and increasing age. This study examines the influence of the presence of chronic somatic diseases and increasing age on symptom dimensions of late-life depression. METHODS: Baseline data of 429 depressed and non-depressed older persons (aged 60-93 years) in the Netherlands Study of Depression in Old Age were used, including symptom dimension scores as assessed with the mood, somatic and motivation subscales of the Inventory of Depressive Symptomatology-Self Report (IDS-SR). Linear regression was performed to investigate the effect of chronic somatic diseases and age on the IDS-SR subscale scores. RESULTS: In depressed older persons a higher somatic disease burden was associated with higher scores on the mood subscale (B = 2.02, p = 0.001), whereas higher age was associated with lower scores on the mood (B = -2.30, p < 0.001) and motivation (B = -1.01, p = 0.006) subscales. In depressed compared with non-depressed persons, a higher somatic disease burden showed no different association with higher scores on the somatic subscale (F(1,12) = 9.2; p = 0.003; partial η(2)=0.022). LIMITATIONS: Because the IDS-SR subscales are specific for old age, it was not feasible to include persons aged < 60 years to investigate differences between earlier and later life. CONCLUSIONS: It seems that neither higher somatic disease burden nor higher age contributes to more severe somatic symptoms in late-life depression. In older old persons aged ≥ 70 years, late-life depression may not be adequately recognized because they may show less mood and motivational symptoms compared with younger old persons.