Recent advances towards overcoming the blood-brain barrier.

The blood-brain barrier (BBB) is a protective element of the neurovascular unit (NVU) surrounded by astrocytes, pericytes, extracellular matrix, and the tight junctional complex, which play a fundamental role in brain homeostasis. Due to its impeccable structural architecture, the BBB is referred to as the brain's gatekeeper, a near-impenetrable barrier to therapeutics. This review summarises the significant strides that have been made in the last 5 years towards circumventing the BBB and developing efficient drug delivery systems. Challenges associated with several CNS disorders related to BBB failure and exploitation of this unique NVU component for targeted treatment of brain-related disorders are also discussed.

Evaluation of sustained-release in-situ injectable gels, containing naproxen sodium, using in vitro, in silico and in vivo analysis.

The study aimed to fabricate naproxen sodium loaded in-situ gels of sodium alginate. Different in-situ gel forming solutions of naproxen sodium and sodium alginate were prepared and gel formation was studied in different physiological ions i.e., CaCl2 and Ca-gluconate. The prepared gel formulations were evaluated for different physical attributes such as gelation time, sol-gel fraction, ATR-FTIR spectroscopy and in silico molecular dynamics (MD) simulations. Drug release studies were carried out in a dialysis membrane using USP dissolution basket apparatus-I. In vivo anti-inflammatory studies were performed in Sprague-Dawley rats having carrageenan-induced hind paw inflammation. Higher polymer concentration in formulations resulted in decreased gelation time and an increased gel fraction. The ATR-FTIR and MD simulation revealed H-bonding between the alginate and naproxen sodium at 3500-3200 cm-1 with a RMSD of ∼2.8 Å and binding free energy ΔGpred (GB) = -10.93 kcal/mol. In vitro drug release studies from F8CAG suggested a sustained release of naproxen sodium. In vivo studies revealed a continuous decrease in swelling degree (≈-5.28 ± 0.210 mm) in inflamed hind paw of Sprague-Dawley rats over 96 h. The in-situ gel forming injectable preparation (F8CAG) offers a sustained release of naproxen sodium in the articular cavity which promises the treatment of chronic inflammatory conditions such as arthritis.

A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing.

Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight about the advances in tablet excipients, manufacturing, analytical techniques and deployment of Quality by Design (QbD). Various excipients offering novel functionalities such as solubility enhancement, super-disintegration, taste masking and drug release modifications have been developed. Furthermore, co-processed multifunctional ready-to-use excipients, particularly for tablet dosage forms, have benefitted manufacturing with shorter processing times. Advances in granulation methods, including moist, thermal adhesion, steam, melt, freeze, foam, reverse wet and pneumatic dry granulation, have been proposed to improve product and process performance. Furthermore, methods for particle engineering including hot melt extrusion, extrusion-spheronization, injection molding, spray drying / congealing, co-precipitation and nanotechnology-based approaches have been employed to produce robust tablet formulations. A wide range of tableting technologies including rapidly disintegrating, matrix, tablet-in-tablet, tablet-in-capsule, multilayer tablets and multiparticulate systems have been developed to achieve customized formulation performance. In addition to conventional invasive characterization methods, novel techniques based on laser, tomography, fluorescence, spectroscopy and acoustic approaches have been developed to assess the physical-mechanical attributes of tablet formulations in a non- or minimally invasive manner. Conventional UV-Visible spectroscopy method has been improved (e.g. fiber-optic probes and UV imaging-based approaches) to efficiently record the dissolution profile of tablet formulations. Numerous modifications in tableting presses have also been made to aid machine product changeover, cleaning, and enhance efficiency and productivity. Various process analytical technologies have been employed to track the formulation properties and critical process parameters. These advances will contribute to a strategy for robust tablet dosage forms with excellent performance attributes.

Determination of Bergenin in Different Parts of Bergenia ciliata using a Validated RP-HPLC Method

Bergenia ciliata (Family: Saxifragaceae) is a folklore remedy for the treatment of various ailments in Asian countries. Bergenin (1) has been isolated as an active constituent in many studies, however, the amount of bergenin has not been determined in all parts of the plant. A simple RP-HPLC method was developed to determine the amount of bergenin in methanol extracts of leaves, rhizomes and roots of the plant. Separation was achieved on an Agilent Eclipse XDB-C18 column maintained at 25 o C using isocratic solvent system (water: methanol: acetic acid; 62.5:37:0.5 v/v/v) adjusted at pH 2 0 at a flow rate of 1.0 mL/min. and detected at 275 nm. Correlation coefficient (0.9952) showed linearity of concentration (5-200 μg/mL) and response. The values of LOD (0.00947 μg/mL) and LOQ (0.02869 μg/mL) indicated that method was sensitive. The recovery of bergenin was 99.99-100% indicating accuracy of method. The methanol extract of rhizomes contained higher amount of bergenin (19.4%) than roots (9.2%) and leaves (6.9%). It is concluded that methanol extract of rhizomes is a better source of bergenin than other parts of the plant. The findings are useful for standardization of bergenin containing extracts and herbal preparations.

Determination of Bergenin in Different Parts of Bergenia ciliata using a Validated RP-HPLC Method

Bergenia ciliata (Family: Saxifragaceae) is a folklore remedy for the treatment of various ailments in Asian countries. Bergenin (1) has been isolated as an active constituent in many studies, however, the amount of bergenin has not been determined in all parts of the plant. A simple RP-HPLC method was developed to determine the amount of bergenin in methanol extracts of leaves, rhizomes and roots of the plant. Separation was achieved on an Agilent Eclipse XDB-C18 column maintained at 25 o C using isocratic solvent system (water: methanol: acetic acid; 62.5:37:0.5 v/v/v) adjusted at pH 2 0 at a flow rate of 1.0 mL/min. and detected at 275 nm. Correlation coefficient (0.9952) showed linearity of concentration (5-200 μg/mL) and response. The values of LOD (0.00947 μg/mL) and LOQ (0.02869 μg/mL) indicated that method was sensitive. The recovery of bergenin was 99.99-100% indicating accuracy of method. The methanol extract of rhizomes contained higher amount of bergenin (19.4%) than roots (9.2%) and leaves (6.9%). It is concluded that methanol extract of rhizomes is a better source of bergenin than other parts of the plant. The findings are useful for standardization of bergenin containing extracts and herbal preparations.

Immediate and Short-Term Outcome of Percutaneous Atrial Septal Defects Closure in Adult Patients.

Background Atrial septal defect secundum (ASD II) is the commonest of the congenital heart diseases in the adult population and the closure of ASD II causes a significant improvement in hemodynamics and the clinical status of the patient. However, it carries certain risks, especially the development of post-closure pulmonary edema and congestive cardiac failure, which may lead to death. Therefore, this study was designed to share our experience and to evaluate the immediate and short-term outcomes of percutaneous closure of ASD II in adult patients presenting at a tertiary care cardiac center in Karachi, Pakistan. Methodology In this study, we included 30 adult (≥ 40 years) patients who underwent percutaneous ASD II closure at the pediatric cardiology department of the National Institute of Cardiovascular Diseases (NICVD), Karachi, Pakistan, between June 1, 2017, and July 31, 2019. Data for this study were extracted from a prospectively collected departmental database. Extracted data for this study consisted of demographic profile, comorbid conditions, echocardiographic findings, cardiac catheterization data, pre and post six-month electrocardiographic findings, and New York Heart Association (NYHA) Functional Classification (FC). Results Out of 30 adult patients, 18 (60%) were female. The mean age of the patients at the time of ASD closure was 51.43 ± 7.09 years, ranging between 40 and 67 years. None of the patients had any post-intervention complications. Mean systolic pulmonary artery pressure (SPAP) on cardiac catheterization pre-implantation was 49.8 ± 16.3 mmHg range was 20-90 mmHg while SPAP immediately after device implantation was 37 ± 11.4 range 20 to 65 mmHg with p<0.001. Mean SPAP on pre-catheterization echocardiography was 58.8 ± 14.3, range 30-95 mmHg, while after six months, the mean SPAP was 34.5 ± 7.2, range 20-45 mmHg, with p<0.001 in 28 (93.3%) patients (in two patients, there was no TR). There was no mortality up till six months after the intervention. The functional class (FC) after six months of the procedure improved in most, 90% (27), of the patients. Conclusion There were no complications immediately after the procedure. After six months, post-procedure SPAP decreased to < 50 mmHg in the majority of patients (96.6%). Functional class (FC) improved in most (90%) of the adult (≥ 40 years) patients undergone percutaneous atrial septal defects closure. Therefore, percutaneous closure of ASD II is a safe and effective procedure for adult patients.

Comparison of Size of Pulmonary Artery and Its Branches on Transthoracic Echocardiography Versus Computed Tomographic Angiography in Patients with Tetralogy of Fallot.

Background Transthoracic echocardiography (TTE) plays a vital role in the assessment of the surgical management of patients with tetralogy of Fallot (TOF). Accurate assessment of the main pulmonary valve annulus, main pulmonary artery (MPA), and branch pulmonary arteries are crucial for decision-making regarding the surgical approach in the form of total correction. It is also important for performing a systemic-to-pulmonary artery shunt operation and affects the outcome. In some patients with poor echogenic windows, it is sometimes difficult to obtain accurate measurements. Cardiac computed tomographic angiography (CTA) can be a superior diagnostic modality. Therefore, the aim of this study was to evaluate the degree of agreement between TTE and CTA in assessing the main pulmonary valve annulus and the size of the MPA and its branches among patients with TOF patients. Methodology Patients above one year of age, with TOF, presented during the study period of six months - from January 1, 2019, to June 30, 2019, were included in the study. All the patients had TTE and cardiac CTA to assess the annulus and the size of the MPA and its branches (right pulmonary artery (RPA) and left pulmonary artery (LPA)). CTA measurement of all parameters was compared with TTE measurement of the same on three different views each by computing the Bland-Altman plot and Pearson correlation coefficients. Results A total of 73 TOF patients were included in this study. The correlation coefficients between CTA and TTE for the measurement of the annulus were 0.767 and 0.833 for the parasternal short-axis view and the subcostal view, respectively. The correlation coefficients between CTA and TTE for the measurement of MPA were 0.820 and 0.866 for the parasternal short-axis view and the suprasternal view, respectively. The correlation coefficients between CTA and TTE for the measurement of RPA were 0.883 and 0.897 for the parasternal short-axis view and the suprasternal view, respectively. Similarly, the correlation coefficients between CTA and TTE for the measurement of LPA were 0.848 and 0.877 for the parasternal short-axis view and the suprasternal view, respectively. Conclusion In conclusion, there is a strong correlation and agreement between cardiac CTA and TTE for the assessment of the annulus and the size of the pulmonary artery (PA) and its branches in patients with TOF.

Early and Intermediate-Term Outcome of Balloon Aortic Valvuloplasty in Children With Aortic Stenosis and Left Ventricular Dysfunction at Tertiary Care Hospital.

Background Left ventricular (LV) dysfunction in patients with aortic valve stenosis (AVS) is seen in two scenarios: in neonates and in elderly patients. Neonatal AVS may present as a congestive cardiac failure (CCF), while older children rarely present with CCF if they have not been diagnosed early. Only a few reports of LV dysfunction with AVS have been described in the literature. However, there is a paucity of data regarding the safety and effectiveness of balloon aortic valvuloplasty (BAV) in children with AVS with LV dysfunction. Therefore, the aim of this study was to evaluate outcomes to establish the safety and effectiveness of BAV in children with AVS and LV dysfunction in improving LV function and survival. Methods A total of 160 BAVs were performed from 2004 to 2017; of these, 41 (25.6%) patients had LV dysfunction. We reviewed these cases, and data were obtained on clinical features, echocardiographic parameters including LV ejection fraction (LVEF) and LV dimensions, LV posterior wall, interventricular septal thickness, pressure gradient across the valve, aortic valve morphology and annulus and aortic insufficiency (AI), and angiographic parameters such as aortic and LV pressures, AI and annulus size, and balloon size. Echocardiography was done before the procedure, one day after intervention, at three months, at six months, and on regular follow-up. Mortality during and after the procedure and at follow-up was reported. Results Children who had undergone BAV for AVS and LV dysfunction within the age range of six to 192 months showed a significant reduction in peak-to-peak pressure gradient (PPG) from 73.5 ± 30 mmHg to 26.7 ± 6.7 mmHg and improvement in LVEF from 32.8 ± 11% to 54.3 ± 12.7% after 24 hours. Instantaneous gradient on echocardiography after three months showed PPG was 29.8 ± 7.7 mmHg and mean LVEF was 63 ± 8.6%. Mean LV end-diastolic pressure was 20.8 ± 4.7 mmHg and decreased to 13 ± 2.4 mmHg. Four patients died, all of whom had severe LV dysfunction - one died during the procedure and three died within six to 20 hours after successful BAV. On average follow-up of 6.4 ± 3.8 years, with a range of three months to 13 years, there was no mortality, pressure gradient increased to 40 ± 16.3 mmHg (range, 20 to 90 mmHg), and three had BAV after one, four, and six years, respectively. There was an increase in AI from mild to moderate in five patients, but they did not require any intervention. Four patients had aortic valve replacement (AVR) with two patients having an increase in pressure gradient and AI after eight and 13 years, respectively. One patient had AI (+3) after BAV had AVR after three years, and one patient who had a very thick and dysplastic aortic valve with LVEF of 20% and pulmonary hypertension (PH) had AVR after six months. Conclusion Patients with AVS who develop LV dysfunction deteriorate and die soon without treatment. Our data suggest that BAV in children with aortic stenosis and LV dysfunction is safe and effective in the normalization of LV function.

Correlation between Echocardiography and Cardiac Catheterization for the Assessment of Pulmonary Hypertension in Pediatric Patients.

Introduction Cardiac catheterization is widely considered the "gold standard" for the diagnosis of pulmonary hypertension. However, its routine use is limited due to its invasive nature. Therefore, the aim of this study was to evaluate the correlation between pulmonary artery pressures obtained by various parameters of transthoracic echocardiography and cardiac catheterization. Methods This study includes 50 consecutive patients with intracardiac shunt lesions diagnosed with severe pulmonary hypertension on echocardiography and admitted for cardiac catheterization at the National Institute of Cardiovascular Diseases (NICVD) in Karachi, Pakistan. Cardiac catheterization and transthoracic echocardiography were performed in all patients simultaneously and systolic (sPAP) and mean pulmonary artery pressure (mPAP) were assessed with both modalities. Correlations and agreement, in terms of Bland-Altman plot, were computed between both modalities for sPAP and mPAP. Results Out of 50 patients, 46% (23) were male and mean age was 7.49 ± 4.45 years. On cardiac catheterization, sPAP was 93.92 ± 17.91 mmHg and mPAP was 67.0 ± 14.28 mmHg. Correlation between cardiac catheterization and echocardiography for the assessment of sPAP was 0.917 (p<0.001), and mPAP was 0.832 (p<0.001) for mean gradient of tricuspid regurgitation (PGTRmean), 0.749 (p<0.001) for peak gradient of pulmonary regurgitation (PGPRpeak), 0.691 (p<0.001) for Acceleration time across right ventricular outflow tract (RVOT), and 0.752 (p<0.001) for end gradient of pulmonary regurgitation (PGPRend). Bland-Altman plot showed moderate agreement between two modalities. Conclusion A positive but modest correlation was observed between hemodynamic parameters of transthoracic echocardiography and cardiac catheterization for assessment of pulmonary artery pressures. Transthoracic echocardiography can reliably be used as an initial non-invasive modality for the assessment of pulmonary artery hypertension and can obviate the need of right heart catheterization in some patient especially with mild pulmonary hypertension.