Investigation of Drug Delivery in Rats via Subcutaneous Injection: Case Study of Pharmacokinetic Modeling of Suspension Formulations

With the rising cost of drug research, “do more with less” has become a new emphasis in the pharmaceutical industry. Consequently, the early analysis of pharmacokinetic/pharmacodynamic, efficacy, and safety parameters for a new drug target is critical for ensuring informed decision-making as soon as possible during the drug discovery process. When absorption, distribution, metabolism, and excretion properties of compounds are suboptimal which is especially true during the early stages of drug discovery, obtaining the desired exposure can be challenging via the most common routes (oral, intravenous). Therefore, subcutaneous (SC) injection is often explored as an alternate route of delivery. Although SC injection is used widely in the industry, information about how to model and predict the absorption of drugs administered via SC injection is not readily available. In the current research, we analyzed the absorption behavior of 12 model compounds covering a wide range of physicochemical properties following SC injection. We introduced a compound-specific parameter, the absorption factor from single SC injections of suspension doses of each compound, to aid in modeling and predicting of drug absorption profiles. The pharmacokinetic models derived in this study are capable of describing and predicting the absorption properties of SC injection for individual compounds.     

Impact of Method of Preparation of Amorphous Solid Dispersions on Mechanical Properties: Comparison of Coprecipitation and Spray Drying

Usage of the amorphous phase of compounds has become the method of choice to overcome oral bioavailability problems related to poor solubility. Due to the unstable nature of glasses, it is clear that the method of preparation of the amorphous glass will have an impact on physical/chemical stability and in turn in vivo performance. The method of preparation can also have a profound impact on the mechanical properties of the amorphous phase. We have explored the impact of preparation method on the mechanical properties of an amorphous solid dispersion using a development compound, GDC-0810. Three methods were used to generate amorphous solid dispersions (ASDs) of 50% GDC-0810 with hydroxypropyl methylcellulose acetate succinate: (1) spray drying, (2) coprecipitation using overhead mixing, and (3) coprecipitation using resonant acoustic mixing. All 3 methods were found to generate ASDs with good phase mixing and similar glass transition temperatures. Coprecipitated ASD powders (overhead mixing and resonant acoustic mixing) demonstrated superior tabletability and flow properties when compared to the spray drying powder. Careful choice of manufacturing process can be used to tune material properties of ASDs to make them more amenable for downstream operations like tableting. Acoustic mixing has been demonstrated as a scalable new method to make ASDs through coprecipitation.     

Techniques and outcomes of transcatheter closure of complex atrial septal defects – Single center experience

Objective

To prospectively study the techniques and outcomes of transcatheter closure of complex Atrial septal defects (ASD).

Study design and settings

Prospective single center study with experience in catheter closure of ASD. All patients with complex ASD suitable for device closure.

Objective

Analysis of outcomes of transcatheter closure of complex ASD in JIPMER Hospital over the past 5-year period.

Methods

Complex ASD was predefined and patients satisfying inclusion and exclusion criteria are included. All the patients had meticulous Transesophageal echocardiography (TEE) imaging beforehand. Modifications of the conventional techniques were allowed on a case per case basis according to operator preference. Successfully intervened patients were followed up clinically.

Results

Out of the 75 patients enrolled, 69 patients had successful device closure (success rate 92%) despite challenging anatomy. Fifty-six (74%) patients had ASD ≥25 mm. Fifteen patients (20%) had defect size ≥35 mm and 20 patients (26.6%) had devices implanted with ≥35 mm waist size. Fifty percent of patients had complete absence of aortic rim and 25% had deficient posterior rim. Twenty percent of patients had malaligned septum. Mean follow up period was 3.2 years.

Conclusions

Trans catheter closure is feasible in anatomically complex substrates of Secundum ASD. Careful case selection, scrupulous imaging protocol, and expertise in modified techniques are mandatory for successful outcomes.     

Effectiveness of technology‐enhanced learning in Endodontic education: a systematic review and meta‐analysis

The aim of the present systematic review was to evaluate the effectiveness of technology‐enhanced learning (TEL) in the field of Endodontics to improve educational outcomes compared to traditional learning methods. Randomized controlled studies published in English were identified from two electronic databases (PubMed and Scopus) up to May 2018. Two authors independently performed study selection, data extraction and assessed the risk of bias (ROB). Any teaching method using TEL was considered as the intervention, and this was compared to traditional methods. The outcome measuring the effectiveness of learning activities was evaluated by Kirkpatrick's four‐level training evaluation model. The four levels of training outcomes are as follows: Reaction, Learning, Behaviour and Results. A meta‐analysis was performed to estimate the standardized mean difference (SMD) by the random effects model. In total, 13 studies were included in the systematic review. Only three studies were assessed as ‘low’ ROB. A meta‐analysis could not be performed in the domains of Reaction and Behaviour. No significant difference was observed in knowledge gain (Learning domain) between TEL and traditional methods (SMD, 0.14 (95% CI ?0.10 to 0.39) I² = 62.7%). Similarly, no difference was observed in performance (Behaviour domain). A variable response was found in attitude (Reaction domain). From the available evidence, it can be concluded that TEL is equally as effective as traditional learning methods.     

Gynaecomastia correction: A review of our experience

Introduction:

Gynaecomastia is a common problem in the male population with a reported prevalence of up to 36%. Various treatment techniques have been described but none have gained universal acceptance. We reviewed all gynaecomastia patients operated on by one consultant over a 7-year period to assess the morbidity and complication rates associated with the procedure.

Materials and Methods:

Clinical notes and outpatient records of all patients who underwent gynaecomastia correction at University Hospital North Staffordshire between 01/10/2001 to 01/10/2009 were retrospectively reviewed. A modified version of the Breast Evaluation Questionnaire was used to assess patients satisfaction with the procedure.

Results:

Twenty-nine patients and a total of 53 breasts were operated on during the study period. Patients underwent either liposuction alone (6 breasts - 11.3%), excision alone (37 breasts - 69.8%) or both excision and liposuction (10 breasts - 18.9%). Twelve operated breasts (22.6%) experienced some form of complication. Minor complications included seroma (2 patients), superficial wound dehiscence (2 patients) and minor bleeding not requiring theatre (3 patients). Two patients developed haematomas requiring evacuation in theatre. No cases of wound infection, major wound dehiscence or revision surgery were encountered. Twenty-six patients (89.7%) returned the patient satisfaction questionnaire. Patients scored an average 4.12 with regards comfort of their chest in different settings, 3.98 with regards chest appearance in different settings, and 4.22 with regards satisfaction levels for themselves and their partner/family. Overall complication rate was 22.6%. Grade III patients experienced the highest complication rate (35.7%), followed by grade II (22.7%) and grade I (17.6%). Overall complication rates among the excision only group was the highest (29.8%) followed by the liposuction only group (16.7%) and the liposuction and excision group (10.0%). There were high satisfaction rates amongst both patients and surgeon. Eleven patients (37.9%) had their outcome classified as ‘excellent’ by the operating surgeon, 16 patients (55.2%) as ‘good’, 1 (3.4%) as ‘satisfactory’ and 1(3.4%) as ‘poor’.

Conclusion:

Gynaecomastia is a complex condition which poses a significant challenge to the plastic surgeon. Despite the possible complications our case series demonstrates that outcomes of operative correction can be favourable and yield high levels of satisfaction from both patient and surgeon.KEY WORDS: Plastic Surgery, University Hospital North Staffordshire, Correction, gynaecomastia, surgery     

Validation of the Maryland Aggregate Pathology Index (MAPI), a pre‐implantation scoring system that predicts graft outcome

Predicting graft outcome after renal transplantation based on donor histological features has remained elusive and is subject to institutional variability. We have shown in a retrospective study that the Maryland Aggregate Pathology Index score reliably predicts graft outcome. We sought to validate the scoring system in our center and a second transplant center. We analyzed 140 deceased donor kidneys pre‐implantation biopsies from center 1 and 65 from center 2. The patients had a mean follow‐up of 695 ± 424 and 656 ± 305 d respectively. Although MAPI scores were similar, there were significant differences in donor and recipient parameters between both centers. Despite this, MAPI was predictive of graft outcome for both centers by Cox univariate, multivariate and time dependent ROC analysis. For center 1 and 2, three yr graft survival within each MAPI group was statistically equivalent. The three‐yr graft survival at center 1 for low, intermediate, and high MAPI groups were 84.3%, 56.5%, and 50.0%, respectively, p ≤ 0.0001, and at center 2 were 83.3%, 33.3%, and 33.3%, p = 0.006. MAPI, which is based on a pre‐implantation biopsy, demonstrated similar predictive and outcome results from both centers. As expanded criteria donors (ECD) criteria have redefined marginal kidneys, MAPI has the potential to further define ECD kidneys, increase utilization, and ultimately improve outcomes.     

Breast vibro-acoustography: initial experience in benign lesions

Background

Functional magnetic resonance imaging (fMRI) analysis is commonly done with cross-correlation analysis (CCA) and the General Linear Model (GLM). Both CCA and GLM techniques, however, typically perform calculations on a per-voxel basis and do not consider relationships neighboring voxels may have. Clustered voxel analyses have then been developed to improve fMRI signal detections by taking advantages of relationships of neighboring voxels. Mean-shift clustering (MSC) is another technique which takes into account properties of neighboring voxels and can be considered for enhancing fMRI activation detection.

Methods

This study examines the adoption of MSC to fMRI analysis. MSC was applied to a Statistical Parameter Image generated with the CCA technique on both simulated and real fMRI data. The MSC technique was then compared with CCA and CCA plus cluster analysis. A range of kernel sizes were used to examine how the technique behaves.

Results

Receiver Operating Characteristic curves shows an improvement over CCA and Cluster analysis. False positive rates are lower with the proposed technique. MSC allows the use of a low intensity threshold and also does not require the use of a cluster size threshold, which improves detection of weak activations and highly focused activations.

Conclusion

The proposed technique shows improved activation detection for both simulated and real Blood Oxygen Level Dependent fMRI data. More detailed studies are required to further develop the proposed technique.