Inhaled dry powder liposomal azithromycin for treatment of chronic lower respiratory tract infection.

A dry powder inhaled liposomal azithromycin formulation was developed for the treatment of chronic respiratory diseases such as cystic fibrosis and bronchiectasis. Key properties including liposome size, charge and encapsulation efficiency powder size, shape, glass transition temperature (Tg), water content and in vitro respiratory deposition were determined. Antimicrobial activity against cystic fibrosis (CF) respiratory pathogens was determined by MIC, MBC and biofilm assays. Cytotoxicity and cellular uptake studies were performed using A549 cells. The average liposome size was 105 nm, charge was 55 mV and encapsulation efficiency was 75 %. The mean powder particle size d[v,50] of 4.54 µm and Mass Median Aerodynamic Diameter (MMAD) was 5.23 µm with a mean Tg of 76˚C and water content of 2.1 %. These excellent physicochemical characteristics were maintained over one year. Liposomal loaded azithromycin demonstrated enhanced activity against P. aeruginosa clinical isolates grown in biofilm. The formulation was rapidly delivered into bacterial cells with > 75 % uptake in 1 h. Rapid uptake into A549 cells via a cholesterol-dependent endocytosis pathway with no cytotoxic effects apparent. These data demonstrate that this formulation could offer benefits over current treatment regimens for people with chronic respiratory infection.

Lessons Learned from the Pandemic in the UAE: Children COVID-19 Vaccine Hesitancy and Its Impact on the Choice of Distance versus Face-to-Face Learning Modalities: An In-Depth Analysis of a National Study.

This study addresses the crucial aspect of childhood COVID-19 vaccination and its impact on parental decisions concerning learning modalities during the pandemic. This study aimed to gauge parental hesitancy towards vaccinating their children and its influence on choosing between distance and face-to-face learning options. Following STROBE guidelines for cross-sectional studies, this study surveyed 1973 parents in the United Arab Emirates using Google Forms during the COVID-19 pandemic. The results revealed that while more than half of the parents (51.6%) were willing to vaccinate their children if the COVID-19 vaccine was accessible and affordable, a significant majority (91.2%) expressed concerns about the rapid vaccine development process, which was the primary reason for vaccine rejection. Interestingly, a sizable portion (55.3%) had experienced online learning in the previous academic term, and, of those, 59.6% believed it negatively influenced their children's academic performance. Consequently, 66.4% expressed intent to shift their children back to face-to-face learning once feasible. Significantly, parents with medical backgrounds were more inclined (91.6%) to opt for face-to-face schooling compared to those without such backgrounds. Logistic regression analysis indicated associations between sociodemographic characteristics, educational level and background, and the decision to return children to face-to-face learning. Interestingly, when it comes to vaccine hesitancy, a noteworthy connection exists between the parents' reluctance to vaccinate their children and their preference for distance learning. In fact, parents who responded negatively to vaccinating their children against COVID-19, if the vaccine was available, showed a clear preference for the distance learning modality (p-value < 0.0001). This study underscores the complex interplay of factors and community perspectives shaping parental acceptance of childhood COVID-19 vaccination. The development pace of vaccines significantly influences parents' attitudes and beliefs about vaccination programs. Parents' medical backgrounds exhibit a clear correlation with their perceptions of sending children back to school safely. This highlights the potential impact of parental medical knowledge on decision making, emphasizing the need to consider parents' professional backgrounds when devising education- and vaccination-related policies.

Public awareness, prevalence, and regulations for the sale of electronic cigarettes in Arab countries: A narrative review.

The majority of the Arab countries have high records of daily tobacco smoking. Electronic cigarettes (e-cigarettes) use has exponentially increased in the past decade in Arab countries. Consumers' willingness to quit smoking traditional cigarettes and their perception of e-cigarettes as a safer alternative to conventional cigarettes have increased the demand for these devices. This narrative review aimed to gather and discuss the available literature on the awareness, prevalence, and sales regulations of e-cigarettes in Arab countries. A search was conducted on electronic databases such as PubMed, Medline, Scopus, and Google Scholar with no time limits until the end of 2021. Some of the recent studies (2019-2021) considered in this review have reported that more than 25% of participants were e-cigarettes users. The prevalence of e-cigarettes has increased drastically with raised awareness of e-cigarettes among the population in these Arab countries. Most of the users of e-cigarettes are young males. In addition, an increase in e-cigarettes use has been reported in females. The policies which regulate trade and sale of e-cigarettes and related products were issued in only three Arab countries. In contrast, regulations for the trade and sale of traditional cigarette products are also applied in some countries to e-cigarette products, banning the sale of e-cigarettes to minors and/or amend smoke-free laws to restrict public use of e-cigarettes. There is a need for a concerted effort to assess the prevalence and significant rise of e-cigarettes consumption in Arab societies to help implement and improve harm reduction policies.

Physicochemical considerations in the formulation development of silicone elastomer vaginal rings releasing 5-nitroimidazole drugs for the treatment of bacterial vaginosis.

Bacterial vaginosis (BV) is a common dysbiosis of the human vaginal microbiota characterized by depletion of hydrogen peroxide and lactic acid-producing Lactobacillus bacteria and an overgrowth of certain facultative anaerobic bacteria. Although short-term cure rates following treatment with frontline antibiotics (most notably oral metronidazole (MNZ), clindamycin vaginal cream, and MNZ vaginal gel) are generally high, longer-term recurrence rates are an issue. The development of vaginal formulations offering continuous/sustained administration of antibiotic drugs over one or more weeks might prove useful in reducing recurrence. Here, we report the manufacture and preclinical testing of matrix-type vaginal rings offering sustained release of four 5-nitroimidazole antimicrobial drugs either being used clinically or having potential in treatment of BV - MNZ, tinidazole (TNZ), secnidazole (SNZ) and ornidazole (ONZ). All four drugs showed good compatibility with a medical-grade addition-cure silicone elastomer based upon thermal analysis experiments, and matrix-type rings containing 250 mg (3.125 %w/w) of each drug were successfully manufactured by reaction injection molding. 28-day in vitro drug release studies demonstrated root-time kinetics, with daily release rates of 25, 22, 9 and 6 mg/day½ for SNZ, ONZ, MNZ and TNZ, respectively. The rank order of drug release from rings correlated with the simple molecular permeability parameter S/V, where S is the measured drug solubility in silicone fluid and V is the drug molecular volume. The relative merits of SNZ and ONZ over MNZ (the current reference treatment) are discussed. The data support development of vaginal rings for sustained release of 5-nitroimidazole compounds for treatment of BV.

Combining microfluidics and coaxial 3D-bioprinting for the manufacturing of diabetic wound healing dressings.

Diabetic foot ulcers (DFUs) are a crucial complication of diabetes, as in a diabetic wound, each step of the physiological healing process is affected. This entails a more easily infectable wound, and delayed tissue regeneration due to the inflammation that occurs, leading to a drastic decrease in the overall patient's quality of life. As a strategy to manage DFUs, skin alternatives and wound dressings are currently receiving a lot of attention as they keep the wound environment "under control", while providing bioactive compounds that help to manage infection and inflammation and promote tissue repair. This has been made possible thanks to the advent of emerging technologies such as 3D Bioprinting to produce skin resembling constructs or microfluidics (MFs) that allows the manufacture of nanoparticles (NPs) that act as drug carriers, in a prompt and less expensive way. In the present proof-of-concept study, the possibility of combining two novel and appealing techniques in the manufacturing of wound dressings has been demonstrated for first time. The novelty of this work consists in the combination of liposomes (LPs) encapsulating the active pharmaceutical ingredient (API) into a hydrogel that is further printed into a three-dimensional scaffold for wound dressing; to the knowledge of the authors this has never been done before. A grid-shaped scaffold has been produced through the coaxial 3D bioprinting technique which has allowed to combine, in one single filament, two different bioinks. The inner core of the filament is a nanocomposite hydrogel consisting of hydroxyethyl cellulose (HEC) and PEGylated LPs encapsulated with thyme oil (TO) manufactured via MFs for the first time. The outer shell of the filament, instead, is represented by a hybrid hydrogel composed of sodium alginate/cellulose nanocrystals (SA/CNC) and enriched with free TO. This provides a combination of two different release ratios of the API, a bulk release for the first 24 h thanks to the free TO in the shell of the filament and a sustained release for up to 10 days provided from the API inside the LPs. Confocal Microscopy verified the actual presence of the LPs inside the scaffold after printing and evaluation using the zone of inhibition test proved the antibacterial activity of the manufactured scaffolds against both Gram-positive and Gram-negative bacteria.

In vitro drug release, mechanical performance and stability testing of a custom silicone elastomer vaginal ring releasing dapivirine and levonorgestrel.

We have previously reported a multipurpose silicone elastomer vaginal ring providing sustained release of dapivirine (an antiretroviral) and levonorgestrel (a progestin) for HIV prevention and hormonal contraception. During initial development, issues arose due to reaction between the ethynyl group in the levonorgestrel molecule and the hydride-functionalised polydimethylsiloxane components in the silicone elastomer formulation. This unwanted reaction occurred both during and to a lesser extent after ring manufacture, impacting the curing process, the mechanical properties of the ring, and the in vitro release of levonorgestrel. Recently, we reported custom silicone elastomer grades that minimise this reaction. In this follow-on study, we describe the manufacture, in vitro drug release, mechanical, and pharmaceutical stability testing of ring formulations prepared from a custom silicone elastomer and containing 200 mg dapivirine and 80, 160, 240 or 320 mg levonorgestrel. The rings showed mechanical properties similar to marketed ring products, sustained in vitro release of both drugs over 30 days in quantities deemed clinically relevant, offered acceptable assay values, and provided good product stability over 15 weeks at 40 °C and 75% relative humidity.

Use of simulated vaginal and menstrual fluids to model in vivo discolouration of silicone elastomer vaginal rings.

Vaginal rings releasing antiretrovirals - either alone or in combination with contraceptive progestins - are being developed for prevention of human immunodeficiency virus (HIV) transmission via vaginal sex. Following Phase I trials, significant discolouration was observed on the surface of investigational silicone elastomer antiretroviral-contraceptive matrix-type vaginal rings containing either 25 mg dapivirine or 200 mg dapivirine plus levonorgestrel. In this study, potential causes of the discolouration have been assessed in vitro using simulated vaginal and menstrual fluids (SVF and SMF, respectively) to model in vivo exposure. The fluid compositions also included hydrogen peroxide (H2O2), hydrogen peroxide plus a copper intrauterine device (IUD), or synthetic dyes (representing personal care and household cleaning products). No discolouration was observed for rings exposed to SVF + hydrogen peroxide (with or without an IUD). However, the SVF + dye compositions showed significant ring discolouration, with staining patterns similar to those observed with rings that had been exposed to highly-coloured personal care and household cleaning products during clinical trial use. Exposure of rings to SMF compositions invariably caused yellow surface discolouration, dark spotting and markings, similar to the staining patterns observed following clinical use. The darker marks on the ring surface were identified as blood debris derived from the SMF. The study indicates that surface discolouration of rings in vivo can be attributed to exposure to menstrual fluid or highly coloured personal care or household cleaning products. Discolouration of the rings was not associated with any specific safety risks for the user, though severe discolouration could potentially impact acceptability and adherence.

Knowledge and beliefs about the use/abuse of oral contraceptive pills among males: A mixed-method explanatory sequential study in community pharmacy settings.

BACKGROUND: Oral contraceptive pills (OCPs) are considered one of the most important birth control methods globally. However, these pills were designed for female administration rather than males. This study was designed to investigate patterns of OCPs use and abuse among Jordanian males, according to the community pharmacists' observations. METHOD: A mixed-method explanatory sequential study was conducted using an online self-administered survey, followed by semi-structured in-depth interviews for registered pharmacists, assistant pharmacists and pharmacy interns. The interviews were utilized using a conceptual framework. Inductive thematic analysis and descriptive/regression analyses were completed using Nvivo and SPSS, respectively. RESULTS: A total of 158 questionnaire responses and 22 interviews were included in our analysis. Around half (48.4%) of the questionnaire responses confirmed that males could use OCPs for hair growth enhancement, muscle gain and acne treatment 12.7%, 31.7% and 4.4%, respectively. Through the interviews, the participating pharmacists highlighted that males use OCPs mostly for bodybuilding purposes, according to recommendations by their coaches at the gym. The most abused OCPs containing estrogen (Ethinyl estradiol) and progestins (Drospirenone or Levonorgestrel). CONCLUSION: This study provided insight into unexpected uses of OCPs by males in Jordan. Community pharmacists have a crucial role in the management of OCPs use and abuse. However, restricted regulations and monitoring must be released and implemented on the community to limit such practices.

COVID-19 Treatment Guidelines: Do They Really Reflect Best Medical Practices to Manage the Pandemic?

SARS-CoV-2 (COVID-19) has been changing the world since December 2019. A comprehensive search into many COVID-19 treatment guidelines was conducted and reported in this article. This is a review paper to probe differences in COVID-19 managing strategies and explore the most common treatment plans among countries. Published guidelines from 23 countries and three references guidelines-until the end of 2020-were included in this article. The majority of COVID-19 treatment options were reported in this review and it includes antiviral drugs, antimalarial drugs, antibiotics, corticosteroids, immunotherapy, anticoagulants, and other pharmacological treatment. The presence of such information from different countries in a single comprehensive review article could help in understanding and speculation of variation in the recommended treatment in each country. This might be related to the cost of medications, the access to the medications, availability of medication that could potentially be useful in managing COVID-19 cases, and the availability/capacity of healthcare facilities. Finally, although there are various treatment groups listed in the published therapeutic guidelines worldwide, unfortunately, there is no evidence for effectiveness of most of these medications in reducing the COVID-19 mortality curve over more than one year of this global pandemic.

COVID-19 Death and BCG Vaccination Programs Worldwide.

Several clinical trials are being conducted worldwide to investigate the protective effect of the bacillus Calmette-Guérin (BCG) vaccine against death in healthcare providers who are working directly with coronavirus disease 2019 (COVID-19) patients. Clinical studies suggested that certain live vaccines, particularly the BCG vaccine, could reduce the mortality due to other diseases caused by non-targeted pathogens, most probably through the nonspecific effects (heterologous effects). By the end of May 2020, the available information on the COVID-19 pandemic indicated the great effect of the BCG vaccine in reducing the number of COVID-19 death cases. The occurrence of death due to COVID-19 was found to be 21-fold lower in countries with a national BCG vaccination policy than in countries without such a policy, based on the medians of COVID-19 death case per 1 million of the population in these two groups of countries (p<0.001, MannWhitney test). Therefore, it can be concluded that the early establishment of a BCG vaccination policy in any country is a key element in reducing the number of COVID-19 and tuberculosis death cases.

Silicone elastomer formulations for improved performance of a multipurpose vaginal ring releasing dapivirine and levonorgestrel.

A dapivirine-releasing silicone elastomer vaginal ring for reducing women's risk of HIV acquisition has recently been approved. A next-generation multipurpose vaginal ring releasing dapivirine and levonorgestrel is currently in development, offering hormonal contraception and HIV prevention from a single device. Previously, we reported challenges with incorporating levonorgestrel into rings manufactured from addition-cure silicone elastomers due to an irreversible chemical reaction between the levonorgestrel molecule and the hydride-functionalised crosslinker component of the silicone elastomer formulation, leading to low drug content assay, cure inhibition, and reduced ring mechanical properties (which may account for the increased incidence of ring expulsion in vivo). Here, we report on the development and testing of various custom silicone elastomer materials specifically formulated to circumvent these issues. After extensive testing of the custom silicones and subsequent manufacture and testing (Shore M hardness, pot life, content assay, oscillatory rheology, mechanical testing) of rings containing both dapivirine and levonorgestrel, a lead candidate formulation was selected that was amenable to practical ring manufacture via injection molding, exhibited no substantial levonorgestrel binding, and offered suitable mechanical properties.

Unforeseen uses of oral contraceptive pills: Exploratory study in Jordanian community pharmacies.

BACKGROUND: The use of oral contraceptive pills (OCPs) as a birth control method is very common worldwide. OCPs have many other labeled non-contraceptive indications, and as a result there is an associated risk of improper use, as with any other medications. This study was designed to assess the unforeseen improper uses of OCPs observed by community pharmacists in Jordan. METHOD: A cross-sectional study design was conducted using a self-administered survey. A convenience sample (n = 380) of Jordanian community pharmacists, were recruited through social media resources. The survey included multiple-choice and open-ended questions. Descriptive statistics and correlation analyses were completed using SPSS. RESULTS: More than half of the recruited pharmacists (55.3%) were female, and the mean age of the participants was 32.58 ± 9.94. The majority of the pharmacists (85%) had good knowledge about the non-contraceptive indications of OCPs. About 53% of them confirmed their exposure to cases of the improper use of OCPs. About 67.5% of the pharmacists who confirmed exposure to such cases, reported the topical use of OCPs for the enhancement of hair growth. Around 15% of those pharmacists stated that OCPs were used to give negative results for addictive drug screening tests. In the event that the pharmacists suspected improper use, more than 90% suggested they would refrain from dispensing the pills. CONCLUSION: This study has spotlighted many unforeseen uses of OCPs in Jordan and highlighted the need for restricted national regulations on the monitoring of OCP prescription/selling patterns in Jordan by policymakers. Moreover, there is a need for the establishment of national educational programs for the Jordanian community regarding the safe proper use of OCPs.

In vitro release testing methods for drug-releasing vaginal rings.

Drug-releasing vaginal rings are torus-shaped devices, generally fabricated from thermoplastic polymers or silicone elastomers, used to administer pharmaceutical drugs to the human vagina for periods typically ranging from three weeks to twelve months. One of the most important product performance tests for vaginal rings is the in vitro release test. Although it has been fifty years since a vaginal ring device was first described in the scientific literature, and despite seven drug-releasing vaginal rings having been approved for market, there is no universally accepted method for testing in vitro drug release, and only one non-compendial shaking incubator method (for the estradiol-releasing ring Estring®) is described in the US Food and Drug Administration's Dissolution Methods Database. Here, for the first time, we critically review the diverse range of test methods that have been described in the scientific literature for testing in vitro release of drug-releasing vaginal rings. Issues around in vitro-in vivo correlation and modelling of in vitro release data are also discussed.

Atmospheric pressure non-thermal plasma exposure reduces Pseudomonas aeruginosa lipopolysaccharide toxicity in vitro and in vivo.

Lipopolysaccharide (LPS) is an endotoxin composed of a polysaccharide and lipid component. It is intrinsically responsible for the pathogenicity of Gram-negative bacteria and is involved in the development of bacterial sepsis. Atmospheric pressure non-thermal plasma is proposed as a potential new approach for the treatment of infected tissue such as chronic wounds, with both antibacterial and wound-healing activities extensively described. Using both the RAW264.7 murine macrophage cell line in vitro assays and the Galleria mellonella insect in vivo toxicity model, the effect non-thermal plasma exposure on LPS-mediated toxicity has been characterised. Short (60 s) non-thermal plasma exposures of Pseudomonas aeruginosa conditioned growth media, membrane lysates and purified P. aeruginosa LPS, resulted in a substantial detoxification and reduction of LPS-induced cytotoxicity in RAW264.7 murine macrophages. Non-thermal plasma exposure (60 s) of purified P. aeruginosa LPS led to a significant (p < 0.05) improvement in the G. mellonella health index (GHI) score, a measure of in vivo toxicity. These findings demonstrate the ability of short plasma exposures to significantly reduce LPS-induced cytotoxicity both in vitro and in vivo; attenuating the toxicity of this important virulence factor intrinsic to the pathogenicity of Gram-negative bacteria.

Towards a dapivirine and levonorgestrel multipurpose vaginal ring: Investigations into the reaction between levonorgestrel and addition-cure silicone elastomers.

With a dapivirine-releasing vaginal ring having successfully completed late-stage clinical testing for HIV prevention and currently undergoing regulatory review, there is now growing interest in next-generation multipurpose prevention technologies that seek to combine antiretroviral and contraceptive drugs within a single product. Here, we focus on ongoing efforts to develop a silicone elastomer vaginal ring releasing both dapivirine and levonorgestrel. Specifically, we evaluate various strategies aimed at both better understanding and reducing the tendency of levonorgestrel to bind with the elastomer, including: (i) formulation and post-manufacturing strategies aimed at reducing the extent of levonorgestrel reaction with addition-cure silicone elastomers; (ii) evaluation of a simple silicone system to model the complex elastomer; (iii) use of model compounds representing the enone and ethinyl moieties of levonorgestrel to probe the mode of addition of levonorgestrel to addition-cure silicone elastomers; and (iv) solution and solid-state 13C NMR analysis to probe the structural features of the levonorgestrel-silicone system. The results demonstrate that both the enone and ethinyl groups within levonorgestrel undergo hydrosilylation reactions with the hydrosiloxane groups in the silicone elastomer leading to covalent binding. The results also highlight potential strategies for further optimising the dapivirine + levonorgestrel silicone vaginal ring formulation to ensure that the levonorgestrel is available for release.