Exploring paediatric oral suspension development: Challenges, requirements, and formulation advancements.

Oral suspension is the most preferred dosage form for the paediatric population because of the difficulties related to solid medications, such as the swallowing limitations, bitter taste, and poor oral bioavailability, which can cause serious impairment to attain a successful treatment. Given the importance of successful therapies, there is a need for safe and effective commercially-available paediatric oral suspension and their characterization. For the latter, it is important to identify safe excipients and preservatives. The paediatric group is a diverse category which includes infants and teenagers, with major pharmacokinetics and pharmacodynamics differences, mainly because of physiological and behavioral variations. Therefore, finding a single formulation for paediatric population remains a challenge, as well asthe formulation of stable-in-time suspension. In addition, drug's dissolving characteristic and permeation, are the main determinants for oral absorption, which are closely related to drug release kinetics from the pharmaceutical form. In this context, drug release profile is an important and limiting step in oral bioavailability, particularly for BCS class II drugs; thus, it is possible to increase bioavailability and minimize adverse effects by changing the release rate of such drugs. This review covers all the aspects for paediatric oral suspension development, and analyses the considerations for excipients selection as a crucial task for effectively choosing a safe and effective pharmaceutical form and correctly dosing paediatric patients.

Learning from an equitable, data-informed response to COVID-19: Translating knowledge into future action and preparation.

Introduction: The COVID-19 pandemic revealed numerous barriers to effectively managing public health crises, including difficulties in using publicly available, community-level data to create learning systems in support of local public health decision responses. Early in the COVID-19 pandemic, a group of health care partners began meeting to learn from their collective experiences. We identified key tools and processes for using data and learning system structures to drive equitable public health decision making throughout different phases of the pandemic. Methods: In fall of 2021, the team developed an initial theory of change directed at achieving herd immunity for COVID-19. The theoretical drivers were explored qualitatively through a series of nine 45-min telephonic interviews conducted with 16 public health and community leaders across the United States. Interview responses were analyzed into key themes to inform potential future practices, tools, and systems. In addition to the interviews, partners in Dallas and Cincinnati reflected on their own COVID-19 experiences. Results: Interview responses fell broadly into four themes that contribute to effective, community driven responses to COVID-19: real-time, accessible data that are mindful of the tension between community transparency and individual privacy; a continued fostering of public trust; adaptable infrastructures and systems; and creating cohesive community coalitions with shared alignment and goals. These themes and partner experiences helped us revise our preliminary theory of change around the importance of community collaboration and trust building and also helped refine the development of the Community Protection Dashboard tool. Conclusions: There was broad agreement amongst public health and community leaders about the key elements of the data and learning systems required to manage public health responses to COVID-19. These findings may be informative for guiding the use of data and learning in the management of future public health crises or population health initiatives.

Method to share learning in real time at scientific meetings: lessons from the IHI-BMJ International Conference on Quality and Safety.

BACKGROUND: Capturing and disseminating key learnings on emerging themes for conference participants is challenging, yet also presents a significant opportunity to distill, share and discuss learning in real time with conference organisers and attendees. The Institute for Healthcare Improvement (IHI) and British Medical Journal (BMJ) collaborate annually to convene a Health Quality and Safety conference attracting 1000 to 3000 attendees each year. AIM: To test a learning system that harvested and synthesised the key lessons shared by conference participants at the 2022 IHI-BMJ Gothenburg Forum, and to disseminate this content. METHODS: Twelve invited Forum attendees collected and shared their 'breakthrough learnings' via electronic survey. Three IHI team members synthesised the participants' responses into themes that were shared and refined in real time at an in-person Forum session including 35 additional participants. RESULTS: Participants shared four learning themes: collaboration and co-production, trust, meaningful communication about data, and broadening the scope of the Science of Improvement field to multi-disciplinary and multi-system approaches. CONCLUSIONS: Collection of key learning on emerging topics of interest to the health system improvement community is feasible and yielded information both for dissemination and real-time learning. While not representing the full scope of the conference learnings, the content resonated with an additional group of reviewers at the conclusion of the conference and has guided planning for the next annual meeting. This approach may be helpful in capturing key themes for discussion and planning by similar improvement communities.

Early IGF-1 Gene Therapy Prevented Oxidative Stress and Cognitive Deficits Induced by Traumatic Brain Injury.

Traumatic Brain Injury (TBI) remains a leading cause of morbidity and mortality in adults under 40 years old. Once primary injury occurs after TBI, neuroinflammation and oxidative stress (OS) are triggered, contributing to the development of many TBI-induced neurological deficits, and reducing the probability of critical trauma patients´ survival. Regardless the research investment on the development of anti-inflammatory and neuroprotective treatments, most pre-clinical studies have failed to report significant effects, probably because of the limited blood brain barrier permeability of no-steroidal or steroidal anti-inflammatory drugs. Lately, neurotrophic factors, such as the insulin-like growth factor 1 (IGF-1), are considered attractive therapeutic alternatives for diverse neurological pathologies, as they are neuromodulators linked to neuroprotection and anti-inflammatory effects. Considering this background, the aim of the present investigation is to test early IGF-1 gene therapy in both OS markers and cognitive deficits induced by TBI. Male Wistar rats were injected via Cisterna Magna with recombinant adenoviral vectors containing the IGF-1 gene cDNA 15 min post-TBI. Animals were sacrificed after 60 min, 24 h or 7 days to study the advanced oxidation protein products (AOPP) and malondialdehyde (MDA) levels, to recognize the protein oxidation damage and lipid peroxidation respectively, in the TBI neighboring brain areas. Cognitive deficits were assessed by evaluating working memory 7 days after TBI. The results reported significant increases of AOPP and MDA levels at 60 min, 24 h, and 7 days after TBI in the prefrontal cortex, motor cortex and hippocampus. In addition, at day 7, TBI also reduced working memory performance. Interestingly, AOPP, and MDA levels in the studied brain areas were significantly reduced after IGF-1 gene therapy that in turn prevented cognitive deficits, restoring TBI-animals working memory performance to similar values regarding control. In conclusion, early IGF-1 gene therapy could be considered a novel therapeutic approach to targeting neuroinflammation as well as to preventing some behavioral deficits related to TBI.

Nanoparticles as Potential Novel Therapies for Urinary Tract Infections.

Urinary tract infection (UTI) is one of the most common reasons for antibiotic treatment. Nevertheless, uropathogens are steadily becoming resistant to currently available therapies. In this context, nanotechnology emerges as an innovative and promising approach among diverse strategies currently under development. In this review we deeply discuss different nanoparticles (NPs) used in UTI treatment, including organic NPs, nanodiamonds, chemical and green synthesized inorganic NPs, and NPs made of composite materials. In addition, we compare the effects of different NPs against uropathogens in vivo and in vitro and discuss their potential impact the in the near future.

Poloxamer 188-Coated Ammonium Methacrylate Copolymer Nanocarriers Enhance Loperamide Permeability across Pgp-Expressing Epithelia.

Loperamide is a µ-opioid agonist with poor gastrointestinal absorption, mainly because of its modest aqueous solubility and being a P-glycoprotein (Pgp) efflux substrate. Nevertheless, studies associated with therapeutic effects strongly suggest that loperamide holds potential pharmacological advantages over traditional µ-opioid agonists commonly used for analgesia. Thus, in this Communication, we assessed in MDCK-hMDR1 cell lines the effects over loperamide uptake and efflux ratio, when loaded into Eudragit RS (ERS) nanocarriers coated with poloxamer 188 (P188). ERS was chosen for enhancing loperamide aqueous dispersibility and P188 as a potential negative Pgp modulator. In uptake assays, it was observed that Pgp limited the accumulation of loperamide into cells and that preincubation with P188, but not coincubation, led to increasing loperamide uptake at a similar extent of Pgp pharmacological inhibition. On the other hand, the efflux ratio displayed no alterations when Pgp was pharmacologically inhibited, whereas ERS/P188 nanocarriers effectively enhanced loperamide uptake and absorptive transepithelial transport. The latter suggests that loperamide transport across cells is significantly influenced by the presence of the unstirred water layer (UWL), which could hinder the visualization of Pgp-efflux effects during transport assays. Thus, results in this work highlight that formulating loperamide into this nanocarrier enhances its uptake and transport permeability.

Colitis actínica de localización cecal. Serie de casos / Actinic colitis of cecal location. Number of cases

Resumen Por definición, la colitis actínica incluye cambios inflamatorios de la mucosa colorrectal secundarios a radioterapia en cercanía a la región tratada. La localización más frecuente es el recto y la indicación más común de radioterapia corresponde a neoplasias de la región pélvica incluidos el recto, la próstata y el cérvix. Se estima que hasta la mitad de los pacientes que reciben radiación pélvica llega a desarrollar síntomas gastrointestinales asociados. Se presentan dos pacientes con metástasis óseas sacroilíacas y pélvicas secundarias a adenocarcinoma de próstata que recibieron radiación en la región lumbosacra y pélvica, ambos pacientes presentaron episodios de deposiciones con sangre que iniciaron tempranamente posterior a la radioterapia. La colonoscopia mostró eritema y ulceración. En el estudio histopatológico se observó un patrón de colitis isquémica, con núcleo y citomegalia, estroma fibroso con cambios reactivos y abundante infiltrado inflamatorio neutrofílico. Estos hallazgos son característicos de la colitis actínica aguda; sin embargo, la localización cecal no ha sido frecuentemente reportada. Aunque al ser el ciego y el íleon terminal móviles de localización pélvica, se convierten en un factor de riesgo para que estos segmentos anatómicos sean susceptibles al impacto directo de la radioterapia. Esta condición, en la fase aguda, es autolimitada y se suele resolver con medidas de soporte. Es indispensable que el personal involucrado en el manejo de estos pacientes conozca esta entidad y los posibles diagnósticos diferenciales.

Abstract By definition, actinic colitis includes inflammatory changes of the colorectal mucosa secondary to radiation therapy of nearby tissue. The most frequent location is the rectum, and the most common indication for radiation therapy is a pelvic region neoplasm in the rectum, prostate or cervix. It is estimated that up to half of patients receiving pelvic radiation go on to develop associated gastrointestinal symptoms. We present two patients with sacroiliac and pelvic bone metastases secondary to prostate adenocarcinoma who received radiation in the lumbosacral and pelvic region. Both patients developed bloody stools soon after radiation therapy. Colonoscopy showed erythema and ulceration, and histopathology found a pattern of ischemic colitis with nucleus and cytomegalovirus infection, fibrous stroma with reactive changes and abundant inflammatory infiltration of neutrophils. These findings are characteristic of acute actinic colitis, but the cecal location has not been reported frequently. Nevertheless, the pelvic location of the cecum and the terminal ileum puts these anatomical segments at risk from the direct impact of radiation therapy. In the acute phase, this condition, is self-limiting and usually resolves with support measures. It is essential that the personnel involved in the management of these patients be aware of this entity and its possible differential diagnoses.

A mechanistic approach for the optimization of loperamide loaded nanocarriers characterization: Diafiltration and mathematical modeling advantages.

Oral bioavailability of loperamide is restricted by its limited absorption in the gastrointestinal tract due to its poor aqueous solubility and its P-glycoprotein (Pgp) substrate characteristic. In addition, ammonium methacrylate copolymers have shown to have mucoadhesive properties, whereas poloxamer 188, has been suggested as a Pgp inhibitor. Thus, in this work, we evaluate conditions that affect physicochemical parameters of ammonium methacrylate/poloxamer 188-based nanocarriers loaded with loperamide hydrochloride. Nanocarriers were synthesized by nanoprecipitation, enhancing loperamide encapsulation efficiency by modifying the aqueous phase to basic pH. The isolation of the non-encapsulated drug fraction from the nanocarriers-incorporated fraction was conducted by centrifugation, ultrafiltration, vacuum filtration and diafiltration. The last method was effective in providing a deeper understanding of drug-nanocarrier loading and interactions by means of modeling the data obtained by it. Through diafiltration, it was determined an encapsulation efficiency of about 93%, from which a 38% ±6 was shown to be reversibly (thermodynamic interaction) and a 62% ±6 irreversibly (kinetic interaction) bound. Finally, release profiles were assessed through empirical and semi-empirical modeling, showing a biphasic release behavior (burst effect 11.34% and total release at 6 h = 33% ±1). Thus, encapsulation efficiency and release profile were shown to have a strong mathematical modeling-based correlation, providing the mechanistic approach presented in this article a solid support for future translational investigations.

Finding key nanoprecipitation variables for achieving uniform polymeric nanoparticles using neurofuzzy logic technology.

Nanoprecipitation is a simple and fast method to produce polymeric nanoparticles (Np); however, most applications require filtration or another separation technique to isolate the nanosuspension from aggregates or polydisperse particle production. In order to avoid variability introduced by these additional steps, we report here a systematic study of the process to yield monomodal and uniform Np production with the nanoprecipitation method. To further identify key variables and their interactions, we used artificial neural networks (ANN) to investigate the multiple variables which influence the process. In this work, a polymethacrylate derivative was used for Np (NpERS) and a database with several formulations and conditions was developed for the ANN model. The resulting ANN model had a high predictability (> 70%) for NpERS characteristics measured (mean size, PDI, zeta potential, and number of particle populations). Moreover, the model identified production variables leading to polymer supersaturation, such as mixing time and turbulence, as key in achieving monomodal and uniform NpERS in one production step. Polymer concentration and type of solvent, modifiers of polymer diffusion and supersaturation, were also shown to control NpERS characteristics. The ANN study allowed the identification of key variables and their interactions and resulted in a predictive model to study the NpERS production by nanoprecipitation. In turn, we have achieved an optimized method to yield uniform NpERS which could pave way for polymeric nanoparticle production methods with potential in biological and drug delivery applications.

Nanomedicine and nanotoxicology: the pros and cons for neurodegeneration and brain cancer.

Current strategies for brain diseases are mostly symptomatic and noncurative. Nanotechnology has the potential to facilitate the transport of drugs across the blood-brain barrier and to enhance their pharmacokinetic profile. However, to reach clinical application, an understanding of nanoneurotoxicity in terms of oxidative stress and inflammation is required. Emerging evidence has also shown that nanoparticles have the ability to alter autophagy, which can induce inflammation and oxidative stress, or vice versa. These effects may increase neurodegenerative processes damage, but on the other hand, they may have benefits for brain cancer therapies. In this review, we emphasize how nanomaterials may induce neurotoxic effects focusing on neurodegeneration, and how these effects could be exploited toward brain cancer treatment.

Diabetes-induced changes in the alternative splicing of the slo gene in corporal tissue.

OBJECTIVES: Erectile dysfunction is a common diabetic complication. Preclinical studies have documented that the Slo gene (encoding the BK or Maxi-K channel alpha-subunit) plays a critical role in erectile function. Therefore, we determined whether diabetes induces changes in the splicing of the Slo gene relevant to erectile function. METHODS: Reverse transcriptase-polymerase chain reaction was used to compare Slo splice variant expression in corporal tissue excised from control and streptozotocin (STZ)-induced diabetic Fischer F-344 rats. Splice variants were sequenced, characterized by patch clamping, and fused to green fluorescent protein to determine cellular localization. The impact of altered Slo expression on erectile function was further evaluated in vivo. RESULTS: A novel Slo splice variant (SVcyt, with a cytoplasmic location) was predominantly expressed in corporal tissue from control rats. STZ-diabetes caused upregulation of a channel-forming transcript SV0. Preliminary results suggest that SV0 was also more prevalent in the corporal tissue of human diabetic compared with nondiabetic patients. The change in isoform expression in STZ-treated rats was partially reversed by insulin treatment. Intracorporal injection of a plasmid expressing the SV0 transcript, but not SVcyt, restored erectile function in STZ-diabetic rats. CONCLUSIONS: Alternative splicing of the Slo transcript may represent an important compensatory mechanism to increase the ease with which relaxation of corporal tissue may be triggered as a result of a diabetes-related decline in erectile capacity.

Use of 7.5F flexible pediatric cystoscope in the staging and management of urethral stricture disease.

BACKGROUND AND PURPOSE: In the evaluation and treatment of patients with urethral strictures, assessment of the stricture is of paramount importance. To date, urologists have relied on retrograde or antegrade urethrography or both to define stricture length and associated characteristics. Antegrade urethrography typically requires suprapubic access to the bladder, adding to the morbidity of stricture treatment. Herein, we describe the feasibility of using a new method for diagnosing, staging, and managing urethral stricture disease. PATIENTS AND METHODS: Twenty-four men with urethral strictures underwent urethroscopy with a 7.5F, 26-cm "pediatric" flexible cystoscope to stage and manage their disease. Comparison of urethroscopy with retrograde urethrography was made with respect to characterizing the stricture. RESULTS: In all cases, the urethral strictures could be navigated with the 7.5F cystoscope. Documentation of the stricture length and the density of scar tissue and identification and characterization of additional pathology (urethral calculi proximal to the stricture in two patients) were possible in all cases, including four patients with recurrent stricture after complex urethroplasty. CONCLUSION: The 7.5F, 26-cm pediatric flexible cystoscope represents a useful tool in the diagnosis and management of urethral stricture disease. Further studies will be necessary to determine the cost-effectiveness, patient morbidity, and ability to tailor therapy appropriately in comparison with standard retrograde urethrography or voiding cystourethrography.

Pad test by mail for home evaluation of urinary incontinence.

AIMS: To present a simple, cost-effective, and convenient method of home pad test using the mail system and evaluating change in pad weight over time. MATERIALS AND METHODS: A series of nine kinds of commonly available commercial brands of urinary incontinence pads ranging from thin liners less than 10 g in dry weight to large diapers weighing over 100 g each were assembled. Two or three of each variety were individually weighed on an OHAUS LS2000 Portable Standard scale accurate to +/- 1 g. The pads were then wet uniformly with 20 cc of saline, placed individually in sealable plastic bags, sealed, and reweighed. Random groups of three pads were mailed by standard 1st class mail to the Urocenter of New York. The sealed pads were reweighed at 8 and 14 days from the original wetting. Concurrently, ten incontinence pads soiled with urine were similarly examined to confirm that there would be no detectable difference between urine and saline for the purpose of the study. In the second part of the study, 20 pads of the same type (13 inch-long pads with absorbent gel) were divided into 4 groups of 5 pads; each group was uniformly wet with 5, 10, 20, or 50 g of saline. These pads were mailed and reweighed at 7 and 14 days from the initial wetting. RESULTS: Twenty-four pads were used in the first part of the study. The dry weights of 22/24 (92%) of the pads were within 2 g of the average weight for their brand. At the first reweighing, 22 pads (92%) weighed within 2 g of their initial wet weights (Fig. 1). Only two pads on day 8 differed substantially from their initial weights: one pad appeared to have lost 4 g and another one 9 g. On day 14, 23/24 pads remained within 1 g of their day 8 weight and 1 differed by 2 g, and the total weight of the 24 pads on day 14 was only 4 g different from their initial weight (P = 0.71, Fig. 1). The soiled pads exhibited weight changes that were indistinguishable from the saline pads. The average cost of mailing the pads by 1st class mail was $4 and the average length of time in the mail was 5 days +/- 1 day. In the second part of the study, 18/20 pads had lost less than 1 g at 1 week, and at 2 weeks, 19/20 had lost less than 2 g when compared to their initial weights (Fig. 2). One pad had lost 3 g. Pads in the low volume groups (5 and 10 g) lost an average of 1.4 and 1.2 g, respectively, while pads in the high volume groups (20, 50 g) lost an average of 1.8 and 2 g at 2 weeks. CONCLUSIONS: Dry pads of any single brand have a relatively standard weight that varies insignificantly between pads. Up to 2 weeks of delay in the weighing of individually sealed pads does not significantly affect the clinical measurement of weight at a variety of low (5 g) or high (50 g) volumes of simulated incontinence. Home pad test using the mail system is a feasible, inexpensive, and clinically accurate method of evaluating incontinence. Patients can be instructed in techniques for home pad test, allowing for greater compliance, and convenience for both physicians and patients.

Critical surgical techniques for radical perineal prostatectomy.

PURPOSE: Radical perineal prostatectomy was historically the surgical treatment of choice for localized adenocarcinoma of the prostate until the 1980s when radical retropubic prostatectomy began to gain popularity. Nevertheless, the perineal approach possesses advantages that prompt resurgence in the interest of this classic operation. We review the relevant anatomy and our modified technique of performing a successful radical perineal prostatectomy. MATERIALS AND METHODS: The English literature pertaining to the different surgical approaches to radical perineal prostatectomy was reviewed through PubMed. Attention was paid to its indications, anatomical significance and various surgical techniques. RESULTS: Studies demonstrate no difference in the incidence of positive surgical margins and biochemical recurrence between radical retropubic and perineal prostatectomies. Furthermore, the perineal approach avoids the dorsal venous complex and better facilitates the vesicourethral anastomosis in the face of minimal pain and requirement for transfusion. We use a modified Belt approach, aiming to yield the most optimal outcome with minimal morbidity. A meticulous anatomical approach is warranted if complications such as rectal injury, incontinence and erectile dysfunction are to be minimized. CONCLUSIONS: With careful preoperative evaluation, selected patients should benefit from radical perineal prostatectomy for the management of localized prostate cancer. Familiarity with this specialized technique should be an immeasurable addition to any armamentarium in the therapy of prostatic diseases.