Preparation of celecoxib loaded bioactive glass chitosan composite hydrogels: a simple approach for therapeutic delivery of NSAIDs.

Arthritis causes inflammatory damage to joints and connective tissues. In the treatment of arthritis, precise and controlled drug delivery to the target site is among the frontline research approaches. In the present research work, celecoxib drug and bioactive glass incorporated chitosan hydrogels were fabricated by the freeze gelation method. Fourier transform infrared spectroscopy, scanning electron microscopy, and thermogravimetric analysis/differential scanning calorimetry techniques were used to characterize the hydrogels. Different kinetic models were applied to study the drug release kinetics. The celecoxib release was mainly controlled by a Fickian diffusion process followed by the Higuchi model. Maximum 86.2% drug entrapment was observed in 20 mg drug-loaded hydrogel and its swelling ratio was 115.5% in 28 d. Good hydrophilicity, good drug entrapment efficiency, and moderate drug release patterns of hydrogels can make them suitable for sustained drug release. The cytocompatibility of hydrogels was established by performing an MTT assay on the BHK-21 fibroblast cell line. The promising results have proved that hydrogels can be considered potential material for the slow release of anti-inflammatory drug at the target site in arthritis.

Novel Hydrophilic Oligomer-Crosslinked Gelatin-Based Hydrogels for Biomedical Applications.

Gelatin-based hydrogels have shown good injectability and biocompatibility and have been broadly used for drug delivery and tissue regeneration. However, their low mechanical strengths and fast degradation rates must be modified for long-term implantation applications. With an aim to develop mechanically stable hydrogels, reactive anhydride-based oligomers were developed and used to fabricate gelatin-based crosslinked hydrogels in this study. A cascade of hydrophilic oligomers containing reactive anhydride groups was synthesized by free radical polymerization. These oligomers varied in degree of reactivity, comonomer composition, and showed low molecular weights (Mn < 5 kDa). The reactive oligomers were utilized to fabricate hydrogels that differed in their mechanical strengths and degradation profiles. These formulations exhibited good cytocompatibility with human adipose tissue-derived stem cells (hADCs). In conclusion, the reactive MA-containing oligomers were successfully synthesized and utilized for the development of oligomer-crosslinked hydrogels. Such oligomer-crosslinked gelatin-based hydrogels hold promise as drug or cell carriers in various biomedical applications.

Correct administration aid for oral liquid medicines: Is a household spoon the right choice?

Background: Correct medicine dosing is an important component in the safe and effective delivery of medicines, particularly for the pediatric population. However, there is a scarcity of public campaigns on the correct administration and choice of dosing aids for oral liquid dosage form in many countries, leading to medicine safety issues and therapeutic failures. Methods: The study targeted the assessment of the knowledge and practice of university students. It utilizes pre- and post-intervention surveys administered through google forms as a survey tool during online zoom and in-person sessions. The intervention included a short video presentation detailing the selection and use of medicine spoons and other aids for the administration of oral liquid dosage. The Fischer Exact test was used to assess the pre- and post-test shift of responses. Results: Nine-degree programs were engaged in the activity, and 108 students attended this health awareness activity after obtaining formal consent. A significant decline (CI = 95%, **** p-value < 0.05) in the choice of selecting tablespoon and a shift to a low-volume spoon, as well as rejection of an entire variety of household spoons, were observed. A significant improvement in the correct naming of spoons, the meaning of the abbreviation "tsp," and the correct volume of a standard teaspoon were also observed with a p-value of <0.001. Conclusion: A deficit in the knowledge of the proper use of measuring devices for oral liquid medicines in the educated population was observed, which can be enhanced through simple tools like short video presentations and awareness seminars.

Availability of Access, Watch, and Reserve groups of essential antibiotics: a cross-sectional survey.

Background: Lower-middle income countries face drastic challenges in Access to essential medicines. Data regarding Pakistan is scarce with no comprehensive study in this regard. The objectives of the study are to document and compare public and private sector availability of all essential antibiotics as well as to conduct a comparison among the AWaRe groups. Methods: The study analyzed 103 essential antibiotics comprising 51 Access, 29 Watch, 6 Reserve, and 17 anti-tuberculosis drugs from 15th August to 10th September 2020 in Lahore, Pakistan. It included on-spot physical availability and availability trend surveys. The survey sites included five public tertiary care hospitals with one as anchor and four randomly selected. Their hospital pharmacies and one randomly selected private retail pharmacy from the vicinity each hospital comprised the ten sampling sites. Percentage availability for each antibiotic was categorized as high (>80%), fairly high (50-80%), low (30-<50%), very low (<30->0%), and not available (0%). Results: The mean percentage on-spot availability was 23.76% ± 5.19 (14-25%) for public facilities and 59.20% ± 4.45 (54-66%) for private sector retail pharmacies. The overall percentage of available essential antibiotics varied significantly (p** < 0.001) in public and private sector sampling sites. Except for the Watch group, all other groups showed the mode of 0% availability. A significant difference (p**** < 0.00001) was seen in percentage availability by Access, Watch, Reserve, and anti-TB-all groups of essential antibiotics. The availability trend survey revealed a list of 18 medicines as 'as never been available', and five medicines were 'not available for 5 years or more than 5 years.' Fourteen medicines as 'never been heard.' Conclusion: Non-availability of essential medicines is a significant public health challenge at public-sector facilities in Pakistan. It was observed that a number of essential antibiotics were not available in both public and private sectors. A number of corrective strategies are required. This includes the engagement of stakeholder and government bodies. This can help to improve supply chain barriers.

A Prospective Study of Medication Surveillance of a Pediatric Tertiary Care Hospital in Lahore, Pakistan.

PURPOSE: Several studies have shown that polypharmacy is the main cause of drug interactions, and the prevalence and the level of the severity varied with the duration of stay in the hospital, sex and race of the patients. The aims of this investigation were to identify the drug-drug interactions in hospitalized pediatric patients associated with polypharmacy, and to categorize the drug interactions in pharmacokinetic or pharmacodynamic interactions according to their level of severity. METHODS: A cross-sectional, prospective analytical study was performed at a pediatric tertiary care hospital in Lahore, Pakistan for the duration of 4 months, which included prescription orders for 300 patients. Data were collected from patient medical files about previous and current medication history. Drug interactions were analyzed using interaction checker on Medscape and categorized according to the severity levels. RESULTS: Out of 300 patients, the occurrence of drug interactions was found in 157 (52.3%) patients, while in 143 (47.7%), no interaction was found. Among these interactions, 50.7% were pharmacodynamic interactions, and 49.30% were pharmacokinetic interactions. Eighty-one percent of prescription orders with drug interactions contained more than three drugs, and 11.9% of interactions were severe. The majority of interactions were of amikacin-vancomycin, piroxicam-captopril and captopril-ciprofloxacin. CONCLUSION: Most of the interactions were moderate among patients with multiple drug prescriptions. The drug interactions can be minimized by providing special patient monitoring and adequate management with prior knowledge of these drug interaction.

Dose Tailoring of Vancomycin Through Population Pharmacokinetic Modeling Among Surgical Patients in Pakistan.

Background: Vancomycin is a narrow therapeutic agent, and it is necessary to optimize the dose to achieve safe therapeutic outcomes. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize the dose among surgical patients in Pakistan. Methods: Plasma concentration data of 176 samples collected from 58 surgical patients treated with vancomycin were used in this study. A population pharmacokinetic model was developed on NONMEM® using plasma concentration-time data. The effect of all available covariates was evaluated on the pharmacokinetic parameters of vancomycin by stepwise covariate modeling. The final model was evaluated using bootstrap, goodness-of-fit plots, and visual predictive checks. Results: The pharmacokinetics of vancomycin followed a one-compartment model with first-order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.45 L/h and 22.6 l, respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and body weight of the patients; however, no covariate was significant for its effect on the volume of distribution. Dose tailoring was performed by simulating dosage regimens at a steady state based on the CRCL of the patients. The tailored doses were 400, 600, 800, and 1,000 mg for patients with a CRCL of 20, 60, 100, and 140 ml/min, respectively. Conclusion: Vancomycin CL is influenced by CRCL and body weight of the patient. This model can be helpful for the dose tailoring of vancomycin based on renal status in Pakistani patients.

Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability.

Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, in vivo pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by ∼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, Cmax, and lower Tmax than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.

Availability of essential medicines in Pakistan-A comprehensive document analysis.

INTRODUCTION: Access to essential medicines (EMs) is a basic human right. Non-availability and shortages of EMs are reported for Pakistan but there is insufficient data to define the nature and magnitude of this problem. The current study is designed to systematically analyze the medicines included in the National Essential Medicines List (NEML) for their availability through comprehensive document analysis. METHODS: An expanded list of medicinal items was developed using the NEML of Pakistan (2018) to enlist individual medicines with their specifications. Registration status of the medicines was searched using three publicly accessible information sources; Pharmaguide 25th Edition, 2018-19, the on-line Drug Information System, and the Mobile Application Pharmapedia followed by a later 3-step validation of the data. The unregistered EMs were then further categorized into three subgroups in accordance with their possible remedial strategies. FINDINGS: The 19 studied categories comprised 690 EMs and it was found that 179 (26%) of these EMs don not have a registration status. However, it was also identified that the availability of 47 (26.2%) out of 179 unregistered EMs can be enssured by strengthening compounding services, and prioritizing registration of age-appropriate formulations. Availability of another 39 (21.7%) such medicines can be ensured by revising the NEML or the product registrations for the slight differences in their different specifications. The categories showing high proportion of unregistered medicines included anti-Parkinson's medicines (100%), antidotes and other substances used in poisoning (60%), diuretics (47%), anticonvulsants/antiepileptics (42%), hormones and other endocrine medicines and contraceptives (38%), medicines for mental and behavioral disorders (30%), anti-infectives (27%), medicines for pain and palliative care (26%), medicines for neonatal care (25%), medicines for diseases of joint (25%), gastrointestinal medicines (24%) and cardiovascular medicines (15%). CONCLUSION: The study shows the absence of registration status of a significant number of EMs in Pakistan. This could be major barrier in their access. Strategies are needed to strengthen the processes of their registration on priority basis.

Osteogenic Potential of Mesenchymal Stem Cells from Adipose Tissue, Bone Marrow and Hair Follicle Outer Root Sheath in a 3D Crosslinked Gelatin-Based Hydrogel.

Bone transplantation is regarded as the preferred therapy to treat a variety of bone defects. Autologous bone tissue is often lacking at the source, and the mesenchymal stem cells (MSCs) responsible for bone repair mechanisms are extracted by invasive procedures. This study explores the potential of autologous mesenchymal stem cells derived from the hair follicle outer root sheath (MSCORS). We demonstrated that MSCORS have a remarkable capacity to differentiate in vitro towards the osteogenic lineage. Indeed, when combined with a novel gelatin-based hydrogel called Osteogel, they provided additional osteoinductive cues in vitro that may pave the way for future application in bone regeneration. MSCORS were also compared to MSCs from adipose tissue (ADMSC) and bone marrow (BMMSC) in a 3D Osteogel model. We analyzed gel plasticity, cell phenotype, cell viability, and differentiation capacity towards the osteogenic lineage by measuring alkaline phosphatase (ALP) activity, calcium deposition, and specific gene expression. The novel injectable hydrogel filled an irregularly shaped lesion in a porcine wound model displaying high plasticity. MSCORS in Osteogel showed a higher osteo-commitment in terms of calcium deposition and expression dynamics of OCN, BMP2, and PPARG when compared to ADMSC and BMMSC, whilst displaying comparable cell viability and ALP activity. In conclusion, autologous MSCORS combined with our novel gelatin-based hydrogel displayed a high capacity for differentiation towards the osteogenic lineage and are acquired by non-invasive procedures, therefore qualifying as a suitable and expandable novel approach in the field of bone regeneration therapy.

Injectable oligomer-cross-linked gelatine hydrogels via anhydride-amine-conjugation.

Injectable gelatine-based hydrogels are valuable tools for drug and cell delivery due to their extracellular matrix-like properties that can be adjusted by the degree of cross-linking. We have established anhydride-containing oligomers for the cross-linking of gelatine via anhydride-amine-conjugation. So far, this conversion required conditions not compatible with cell encapsulation or in vivo injection. In order to overcome this limitation, we developed an array of quarter-oligomers varying in comonomer composition and contents of reactive anhydride units reactive towards amine groups under physiological conditions. The oligomers were of low molecular weight (Mn < 5 kDa) with a high degree of chemically intact anhydrides. Chemical comonomer composition was determined by 1H-NMR. Dissolutions experiments confirmed improved hydrophilicity of the synthesized oligomers over our established compositions. Injectable formulations are described utilizing cytocompatible concentrations of constituent materials and proton-scavenging base. Degree of cross-linking and stiffness of injectable hydrogels were controlled by composition. The gels hold promise as injectable drug or cell carrier and as bioink.

Formulation of Phaseolus vulgaris L. cream and its characterization.

Red kidney beans have antioxidant effect and thereby can help in skin smoothening, moisturizing, whitening and have anti-wrinkles effect. The study was based on the formulation of a stable w/o emulsion possessing extract of Phaseolus vulgaris L. seeds, using paraffin oil with the aim to investigate its effect on various skin parameters. The extract, achieved by concentrating ethanolic extract of red kidney beans was embedded in the internal aqueous part of w/o emulsion. An active formulation possessing concentrated extract of red kidney beans and a placebo formulation having no active material in the aqueous phase were formulated and placed at various conditions for the duration of 28 days, to observe the stability of cream. The placebo and formulation were stable at different storage conditions in terms of phase separation and colour changes. Minute liquefaction was observed from 21stday up to 28th day in formulations which were kept at 40°C +75% RH (relative humidity). With the passage of time significant changes were observed in formulation pH while insignificant changes were observed at basic pH. Different effects of creams i.e., placebo and formulations were observed on the human skin by applying them on the volunteer's cheeks for about 8 weeks. A stable w/o emulsion can be formulated by using red kidney beans' extract without any phase separation, liquefaction and colour change over 28 days storage.

Formulation, characterization and in vitro evaluation of antifungal activity of Nystatin micro emulsion for topical application.

The current research aims at development and assessment of o/w nystatin microemulsion. The pseudoternary phase diagrams were developed to determine microemulsion existence regions by water titration method. Nystatin was liquefied in the blend of oil phase, surfactant and cosurfactant. Microemulsion was made by deliberate mixing of water and stirring in this blend. The S-mix (surfactant-cosurfactant mixtures) of the ratio 1:2 was found better than 1:1 and 2:1 S-mix ratios. In vitro permeation studies by Franz diffusion cell revealed faster rate of nystatin release from such microemulsion (5.37µg/cm2/h) as compared to nystrin (4.79µg/cm2/h), a commercially available aqueous suspension. Kinetic modeling demonstrated zero order drug release and release mechanism found to be anomalous i.e. superposition of dispersion and swelling controlled drug release. Antifungal activity was performed using well diffusion method in vitro against Candida albicans cultures grown on Sabouraud's dextrose agar. The results also confirmed the high diffusion rate of drug from microemulsion as compared to aqueous suspension. The outcomes of this study propose that topical microemulsion of nystatin provides better antifungal activity as compared to emulsion gels or aqueous suspensions.

Evaluation of gender difference in pharmacokinetics of Candesartan cilexetil in the fasted state by RP-HPLC: A single dose comparative study.

To compare the pharmacokinetics of candesartan cilexetil in healthy male and female volunteers in order to identify possible influence of gender and to improve therapeutic outcomes, an HPLC method for the quantification of candesartan cilexetil was developed and validated. Total of 16 volunteers (8 male and 8 female) were registered. Candesartan cilexetil 16 mg was administered orally to all the volunteers and blood samples were collected at different time intervals between 0-72 hours. Plasma was separated and analysed by HPLC method. Pharmacokinetic parameters were calculated by using APO software MW/PHARM version 3.02 and compared in male and female volunteers. The developed HPLC method fulfils the criteria for linearity, accuracy and precision described in EMA guideline. The values for absorption rate constant (Ka), maximum plasma concentration (Cmax), volume of distribution (Vd) and Clearance (CL) were similar in male and female volunteers. No influence of gender was observed on overall pharmacokinetics of candesartan cilexetil. Therefore, no need for dose optimization while administering candesartan cilexetil in male and female patients was found based on the results of this study.

Multi-Functional Macromers for Hydrogel Design in Biomedical Engineering and Regenerative Medicine.

Contemporary biomaterials are expected to provide tailored mechanical, biological and structural cues to encapsulated or invading cells in regenerative applications. In addition, the degradative properties of the material also have to be adjustable to the desired application. Oligo- or polymeric building blocks that can be further cross-linked into hydrogel networks, here addressed as macromers, appear as the prime option to assemble gels with the necessary degrees of freedom in the adjustment of the mentioned key parameters. Recent developments in the design of multi-functional macromers with two or more chemically different types of functionalities are summarized and discussed in this review illustrating recent trends in the development of advanced hydrogel building blocks for regenerative applications.

Assessment of sex differences in Pharmacokinetics of carvedilol in human.

Carvedilol is an anti-hypertensive agent capable of blocking both alph (α) and beta (ß) receptors used to preclude cardiac arrhythmias and angina. The study was designed to evaluate the Pharmacokinetics of carvedilol in human male and female volunteers. Healthy male and female (twenty each) volunteers were finalized for the study after preliminarily clinical examination. Blood samples were collected at specific time intervals after giving an oral dose of 12.5mg carvedilol, separated the plasma and placed at -80°C until analysis. Estimation of carvedilol in human plasma was accomplished by High performance liquid chromatographic (HPLC) method using fluorescent detector. Plasma concentration-time curve was used for calculation of pharmacokinetic parameters using two-compartment open model. Mean (SD) values of AUC and Cmax 0.076±0.021ßg.h/ml and 0.024±0.005ßg/mL, respectively) in male differ significantly (P<0.05) from the female 0.197±0.042ßg.h/ml and 0.048±0.02ßg/mL, respectively). Overall, bioavailability of carvedilol was somewhat higher in females than in males, but these differences could be expounded by the lower body weight of female. Conversely, no significant differences were found for tmax, clearance and half-life in male and female. Moreover the ethnicity had significant impact on the Pharmacokinetics of carvedilol in human.