Current status and advances to improving drug delivery in diffuse intrinsic pontine glioma.

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma - DIPG), is the primary cause of brain tumor-related death in pediatric patients. DIPG is characterized by a median survival of <12 months from diagnosis, harboring the worst 5-year survival rate of any cancer. Corticosteroids and radiation are the mainstay of therapy; however, they only provide transient relief from the devastating neurological symptoms. Numerous therapies have been investigated for DIPG, but the majority have been unsuccessful in demonstrating a survival benefit beyond radiation alone. Although many barriers hinder brain drug delivery in DIPG, one of the most significant challenges is the blood-brain barrier (BBB). Therapeutic compounds must possess specific properties to enable efficient passage across the BBB. In brain cancer, the BBB is referred to as the blood-brain tumor barrier (BBTB), where tumors disrupt the structure and function of the BBB, which may provide opportunities for drug delivery. However, the biological characteristics of the brainstem's BBB/BBTB, both under normal physiological conditions and in response to DIPG, are poorly understood, which further complicates treatment. Better characterization of the changes that occur in the BBB/BBTB of DIPG patients is essential, as this informs future treatment strategies. Many novel drug delivery technologies have been investigated to bypass or disrupt the BBB/BBTB, including convection enhanced delivery, focused ultrasound, nanoparticle-mediated delivery, and intranasal delivery, all of which are yet to be clinically established for the treatment of DIPG. Herein, we review what is known about the BBB/BBTB and discuss the current status, limitations, and advances of conventional and novel treatments to improving brain drug delivery in DIPG.

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma.

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy.

Economic burden of advanced lung cancer patients treated by gefitinib alone and combined with chemotherapy in two regions of China.

AIM: To assess the economic burden of different chemotherapies for lung cancer patients and influencing factors in China. MATERIALS AND METHODS: The economic burden of lung cancer, including direct, indirect and intangible costs was measured within three months after diagnosis and treatment. Direct cost included the cost of hospitalization, outpatient visits, out-of-pocket drug purchases, costs of transportation, accommodation and meal expenses while seeking treatments in hospitals. Cost information was attained from questionnaire and patients' medical record. Indirect cost was measured by the patients' and their caregivers' productive days lost due to outpatient visits and hospitalization for lung cancer treatment. Intangible cost was obtained through the willingness-to-pay method from a questionnaire completed by the patient. RESULTS: Among the total cost of CNY71,401.92, direct cost, indirect cost and intangible cost constituted 89.02%, 4.29%, and 6.69% respectively. Educational level, occupation, family income, lung cancer classification, and the city of residence significantly influenced the total cost. LIMITATIONS: Limitations in our study included: First, our follow-up period of three months was relatively short compared to the whole survival period of lung cancer patients. Second, the sample size of the chemotherapy combined with targeted therapy group was not large enough, and the cost data obtained would need confirmation in future studies. Third, participants came from only two localities, which may somewhat limit the representativeness of the study results for the whole of China. CONCLUSIONS: The economic burden of lung cancer treatment mainly came from the cost of the drugs. Patients taking chemotherapy had significantly higher cost compared to patients using targeted therapy. The cost was generally higher for those with higher educational level, those with higher family income, and those living in an economically more developed city. Patients with NSCLC had higher cost compared to patients with SCLC.

In China, lung cancer is the leading cause of cancer-related deaths and imparts a heavy economic burden. Most lung cancer patients are treated with chemotherapeutic and/of targeted agents because they are usually diagnosed at an advanced stage (IIIB or IV). The use of targeted therapy has achieved high response rates, longer overall survival, and longer progression-free survival compared with conventional chemotherapies. Adverse reactions with targeted therapeutic agents are usually mild compared with conventional chemotherapy. However, targeted drugs for lung cancer are usually more expensive than conventional chemotherapeutic drugs. It should be noted that the adverse effects and toxicities caused by chemotherapeutic drugs are generally more serious compared to targeted drugs; therefore, a number of measures are needed to prevent or relieve these reactions clinically. This can increase the financial burden of lung cancer treatment. Does these two treatments have a different cost? Our results showed that educational level, occupation, family income, classification of lung cancer, and the city of residence significantly influenced the total cost. Patients taking chemotherapy had significantly higher cost compared to patients using targeted therapy. This result suggests that targeted therapy for lung cancer is a better choice than chemotherapy.

Epithelial cells sense local stiffness via Piezo1 mediated cytoskeletal reorganization.

Local substrate stiffness is one of the major mechanical inputs for tissue organization during its development and remodeling. It is widely recognized that adherent cells use transmembrane proteins (integrins) at focal adhesions to translate ECM mechanical cues into intracellular bioprocess. Here we show that epithelial cells respond to substrate stiffening primarily via actin cytoskeleton organization, that requires activation of mechanosensitive Piezo1 channels. Piezo1 Knockdown cells eliminated the actin stress fibers that formed on stiff substrates, while it had minimal effect on cell morphology and spreading area. Inhibition of Piezo1 channels with GsMTx4 also significantly reduced stiffness-induced F-actin reorganization, suggesting Piezo1 mediated cation current plays a role. Activation of Piezo1 channels with specific agonist (Yoda1) resulted in thickening of F-actin fibers and enlargement of FAs on stiffer substrates, whereas it did not affect the formation of nascent FAs that facilitate spreading on the soft substrates. These results demonstrate that Piezo1 functions as a force sensor that couples with actin cytoskeleton to distinguish the substrate stiffness and facilitate epithelial adaptive remodeling.

Current status and advances in esophageal drug delivery technology: influence of physiological, pathophysiological and pharmaceutical factors.

Diseases affecting the esophagus are common. However, targeted drug delivery to the esophagus is challenging due to the anatomy and physiology of this organ. Current pharmacological treatment for esophageal diseases predominantly relies on the off-label use of drugs in various dosage forms, including those for systemic drug delivery (e.g. oral tablets, sublingual tablets, and injections) and topical drug delivery (e.g. metered dose inhaler, viscous solution or suspension, and endoscopic injection into the esophagus). In general, systemic therapy has shown the most efficacy but requires the use of high drug doses to achieve effective concentrations in the esophagus, which increases the risk of adverse effects and toxicity. Topical drug delivery has enormous potential in improving the way we treat patients with acute and chronic esophageal diseases, especially those requiring drugs that have low therapeutic index and/or significant adverse effects to non-targeted organs and tissues. This review will address the physiological, pathophysiological, and pharmaceutical considerations influencing topical drug delivery in the esophagus. The main conventional (e.g. liquid formulations, orodispersible tablets, lozenges, pastilles, troches, chewing gum) and innovative (e.g. stent-based, film-based, nanoparticulate-based) drug delivery approaches will be comprehensively discussed, along with the developments to improve their effectiveness for topical esophageal drug delivery. The translational challenges and future clinical advances of this research will also be discussed.

Extracellular matrix in high-grade serous ovarian cancer: Advances in understanding of carcinogenesis and cancer biology.

High-grade serous ovarian cancer (HGSOC) is notoriously known as the "silent killer" of post-menopausal women as it has an insidious progression and is the deadliest gynaecological cancer. Although a dual origin of HGSOC is now widely accepted, there is growing evidence that most cases of HGSOC originate from the fallopian tube epithelium. In this review, we will address the fallopian tube origin and involvement of the extracellular matrix (ECM) in HGSOC development. There is limited research on the role of ECM at the earliest stages of HGSOC carcinogenesis. Here we aim to synthesise current understanding of the contribution of ECM to each stage of HGSOC development and progression, beginning at serous tubal intraepithelial carcinoma (STIC) precursor lesions and proceeding across key events including dissemination of tumourigenic fallopian tube epithelial cells to the ovary, survival of these cells in peritoneal fluid as multicellular aggregates, and colonisation of the ovary. Likewise, as part of the metastatic series of events, serous ovarian cancer cells survive travel in peritoneal fluid, attach to, migrate across the mesothelium and invade into the sub-mesothelial matrix of secondary sites in the peritoneal cavity. Halting cancer at the pre-metastatic stage and finding ways to stop the dissemination of ovarian cancer cells from the primary site is critical for improving patient survival. The development of drug resistance also contributes to poor survival statistics in HGSOC. In this review, we provide an update on the involvement of the ECM in metastasis and drug resistance in HGSOC. Interplay between different cell-types, growth factor gradients as well as evolving ECM composition and organisation, creates microenvironment conditions that promote metastatic progression and drug resistance of ovarian cancer cells. By understanding ECM involvement in the carcinogenesis and chemoresistance of HGSOC, this may prompt ideas for further research for developing new early diagnostic tests and therapeutic strategies for HGSOC with the end goal of improving patient health outcomes.

Impact of gastric and bowel surgery on gastrointestinal drug delivery.

General surgical procedures on the gastrointestinal tract are commonly performed worldwide. Surgical resections of the stomach, small intestine, or large intestine can have a significant impact on the anatomy and physiological environment of the gastrointestinal tract. These physiological changes can affect the effectiveness of orally administered formulations and drug absorption and, therefore, should be considered in rational drug formulation design for specific pathological conditions that are commonly associated with surgical intervention. For optimal drug delivery, it is important to understand how different surgical procedures affect the short-term and long-term functionality of the gastrointestinal tract. The significance of the surgical intervention is dependent on factors such as the specific region of resection, the degree of the resection, the adaptive and absorptive capacity of the remaining tissue, and the nature of the underlying disease. This review will focus on the common pathological conditions affecting the gastric and bowel regions that may require surgical intervention and the physiological impact of the surgery on gastrointestinal drug delivery. The pharmaceutical considerations for conventional and novel oral drug delivery approaches that may be impacted by general surgical procedures of the gastrointestinal tract will also be addressed.

Impact of pharmacist-initiated educational interventions on improving medication reconciliation practice in geriatric inpatients during hospital admission in Vietnam.

WHAT IS KNOWN AND OBJECTIVE: Unintentional medication discrepancies (UMDs) are common in geriatric patients during care transitions, resulting in frequent undesirable consequences. Medication reconciliation could be a useful practice to prevent or ameliorate UMD. However, this practice in Vietnamese hospitals has not been well established or standardized. This study aims to determine the effect of pharmacist-initiated educational interventions on improving medication reconciliation practice. METHODS: This prospective 6-month pre-and post-study was conducted in two internal medicine wards in a Vietnamese 800-bed public hospital. Pharmacists provided training and short-term support to physicians on medication reconciliation. Primary outcome measures were the proportions of patients with at least one UMD at admission. Secondary outcome measures were the proportions of patients with preventable adverse drug events (pADEs) score ≥0.1 due to these UMDs. Odds ratio and 95% confidence intervals were assessed based on a multivariate logistic regression model. RESULTS AND DISCUSSION: One hundred fifty-two patients were recruited in the pre-intervention phase, and 146 in the post-intervention phase. Following the intervention, the proportion of geriatric patients with ≥1 UMD at admission significantly decreased from 55.3 to 25.3 % (ORadj 0.255, 95% CI: 0.151-0.431). Similarly, the proportion of patients with a pADE ≥0.1 at admission reduced from 44.1 to 11.6% [ORadj 0.188, 95% CI: 0.105-0.340] post-intervention. WHAT IS NEW AND CONCLUSION: Our pharmacist-initiated educational interventions have demonstrated the ability to produce substantial improvement in medication reconciliation practice, reducing UMDs and potential harm. Our approach may provide an alternate option to implement medication reconciliation for jurisdictions with limited healthcare resources.

Physical memory of astrocytes.

Traumatic brain injury (TBI) is a major risk factor for development of neurodegenerative disorders later in life. Short, repetitive, mechanical impacts can lead to pathology that appears days or months later. The cells have a physical "memory" of mechanical events. The origin of this memory is not known. To examine the properties of this memory, we used a microfluidic chip to apply programmed fluid shear pulses to adherent adult rat astrocytes. These caused a transient rise in intracellular Ca2+. In response to repeated stimuli, 6 to 24 hrs apart, the Ca2+ response increased. This effect lasted longer than 24 hrs. The Ca2+ responses were more sensitive to the number of repetitions than to the rest time between stimuli. We found that inhibiting the Ca2+ influx during conditioning stimulus did not eliminate the stress potentiation, suggesting that mechanical deformation during the primary injury is accountable for the later response. The mechanical mechanism that triggers this long term "memory" may act by plastic deformation of the cytoskeleton.

Implementation and Evaluation of Clinical Pharmacy Services on Improving Quality of Prescribing in Geriatric Inpatients in Vietnam: An Example in a Low-Resources Setting.

Purpose: Geriatric inpatients generally have a high risk of drug-related problems (DRP) in prescribing following hospital admission, which are likely to cause negative clinical consequences. This is particularly evident in developing countries such as Vietnam. Therefore, clinical pharmacy service (CPS) aims to identify and resolve these DRPs to improve the quality use of medicines in the older population following hospital admission. Patients and Methods: The study was conducted as a prospective, single-center study implemented at a general public hospital in Hanoi. Patients aged ≥60 years with at least three chronic diseases admitted to the Internal Medicine Department between August 2020 and December 2020 were eligible to be enrolled. A well-trained clinical pharmacist provided a structured CPS to identify any DRP in prescribing for each patient in the study. Clinical pharmacist interventions were then proposed to the attending physicians and documented in the DRP reporting system. Results: A total of 255 DRP were identified in 185 patients during the study period. The most frequent types of DRP were underuse (21.2%), dose too high (12.2%), and contraindication (11.8%). There was a very high rate of approval and uptake by the physicians regarding the interventions proposed by the clinical pharmacist (82.4% fully accepted and 12.5% partially accepted). Of the interventions, 73.4% were clinically relevant (pADE score ≥0.1). In general, 9 out of 10 physicians agreed that CPS has significant benefits for both patients and physicians. Conclusion: Improving clinical pharmacy services can potentially have a positive impact on the quality of prescribing in elderly inpatients. These services should officially be implemented to optimize the quality use of medicines in this population group in Vietnam.

Pathophysiological and Pharmaceutical Considerations for Enhancing the Control of Sarcoptes scabiei in Wombats Through Improved Transdermal Drug Delivery.

Sarcoptic scabiei is an invasive parasitic mite that negatively impacts wombats, causing sarcoptic mange disease, characterized by alopecia, intense pruritus, hyperkeratosis, and eventual mortality. Evidence suggests that wombats may be unable to recovery from infection without the assistance of treatments. Transdermal drug delivery is considered the most ideal route of administration for in situ treatment in free-ranging wombats, as it is non-invasive and avoids the need to capture affected individuals. Although there are effective antiparasitic drugs available, an essential challenge is adequate administration of drugs and sufficient drug retention and absorption when delivered. This review will describe the implications of sarcoptic mange on the physiology of wombats as well as discuss the most widely used antiparasitic drugs to treat S. scabiei (ivermectin, moxidectin, and fluralaner). The prospects for improved absorption of these drugs will be addressed in the context of pathophysiological and pharmaceutical considerations influencing transdermal drug delivery in wombats with sarcoptic mange.

Implementing clinical pharmacy activities in hospital setting in Vietnam: current status from a national survey.

BACKGROUND: Clinical pharmacy activities have evolved over the past decades contributing to all stages of the patient care process, especially in the hospital setting. However, these practice roles may differ to a significant extent depending on the healthcare policy of countries. In Vietnam, the magnitude of adopting clinical pharmacy activities in hospital settings throughout the country is still unknown since these activities have been implemented. This study aimed to ascertain the current status of clinical pharmacy activities performed within the Vietnamese hospital setting. METHODS: A nation-wide survey was conducted from December 2017 to January 2018. Two online questionnaires, one for the Heads of Pharmacy Department and one for clinical pharmacists, were designed based on the national legal regulations about implementing clinical pharmacy activities in the hospital setting. These questionnaires were sent to all hospitals and healthcare facilities with a department of pharmacy. RESULTS: A total of 560 Heads of Pharmacy and 574 clinical pharmacists participated in the study, representing a response rate of 41.2%. Among the participating hospitals, non-patient specific activities were implemented widely across all hospital classes, with pharmacovigilance, medication information, and standard operating procedures development implemented in ≥88% of all hospitals. In contrast, there was a significant variation in the level of implementation of patient-specific activities among hospital classes. With activities such as medication counselling, monitoring of adverse drug reactions, and obtaining patient's medication histories provided at a considerably lower level in between 49 and 57% of hospitals. CONCLUSION: Clinical pharmacy activities have been initiated in most of the surveyed hospitals. In general, clinical pharmacy is more established in higher-class hospitals in Vietnam. However, the current implementation status is focused on non-patient-specific activities, while patient-oriented activities remained insufficiently established.

Unintentional Medication Discrepancies at Admission Among Elderly Inpatients with Chronic Medical Conditions in Vietnam: A Single-Centre Observational Study.

BACKGROUND: Elderly patients are at high risk of unintentional medication discrepancies during transition of care as they are more likely to have multiple comorbidities and chronic diseases that require multiple medications. OBJECTIVE: The aim of the study was to assess the frequency of unintentional medication discrepancies and identify the associated risk factors and potential clinical impact of them in elderly inpatients during hospital admission. PATIENTS AND METHODS: A prospective observational study was conducted from July to December 2018 in an 800-bed geriatric hospital in Hanoi, North Vietnam. Patients over 60 years of age, admitted to one of selected internal medicine wards, taking at least one chronic medication before admission, and staying at least 48 h were eligible for enrollment. Medication discrepancies of chronic medications before and after admission of each participant were identified by a pharmacist using a step-by-step protocol for the medication reconciliation process. The identified discrepancies were then classified as intentional or unintentional by an assessment group comprising a pharmacist and a physician. A logistic regression model was used to identify risk factors of medication discrepancies. RESULTS: Among 192 enrolled patients, 328 medication discrepancies were identified, with 87 (26.5%) identified as unintentional. Nearly a third of enrolled patients (32.3%) had at least one unintentional medication discrepancy. The most common unintentional medication discrepancy was omission of drugs (75.9% of 87 medication discrepancies). The logistic regression analysis revealed a positive association between the number of discrepancies at admission and the type of treatment wards. CONCLUSIONS: Medication discrepancies are common at admission among Vietnamese elderly inpatients. This study highlights the importance of obtaining a comprehensive medication history at hospital admission and supports implementing a medication reconciliation program to reduce the negative impact of medication discrepancy, especially for the elderly population.

Adherent cell remodeling on micropatterns is modulated by Piezo1 channels.

Adherent cells utilize local environmental cues to make decisions on their growth and movement. We have previously shown that HEK293 cells grown on the fibronectin stripe patterns were elongated. Here we show that Piezo1 function is involved in cell spreading. Piezo1 expressing HEK cells plated on fibronectin stripes elongated, while a knockout of Piezo1 eliminated elongation. Inhibiting Piezo1 conductance using GsMTx4 or Gd3+ blocked cell spreading, but the cells grew thin tail-like extensions along the patterns. Images of GFP-tagged Piezo1 showed plaques of Piezo1 moving to the extrusion edges, co-localized with focal adhesions. Surprisingly, in non-spreading cells Piezo1 was located primarily on the nuclear envelope. Inhibiting the Rho-ROCK pathway also reversibly inhibited cell extension indicating that myosin contractility is involved. The growth of thin extrusion tails did not occur in Piezo1 knockout cells suggesting that Piezo1 may have functions besides acting as a cation channel.

Considerations for using optical clearing techniques for 3D imaging of nanoparticle biodistribution.

A key consideration in the clinical translation of nanomedicines is determining their in vivo biodistribution in preclinical studies, which is important for predicting and correlating therapeutic efficacy and safety. There are a number of techniques available for analyzing the in vivo biodistribution of nanoparticles, with each having its own advantages and limitations. However, conventional techniques are limited by their inability to image the three-dimensional (3D) association of nanoparticles with cells, vasculature and other biological structures in whole organs at a subcellular level. Recently, optical clearing techniques have been used to evaluate the biodistribution of nanoparticles by 3D organ imaging. Optical clearing is a procedure that is increasingly being used to improve the imaging of biological tissues, whereby light scattering substances are removed to better match the refractive indices of different tissue layers. The use of optical clearing techniques has the potential to transform the way we evaluate the biodistribution of new and existing nanomedicines, as it allows the visualization of the interaction of nanoparticles with the biological environment in intact tissues. This review will compare the main optical clearing techniques and will address the considerations for the use of these techniques to evaluate nanoparticle biodistribution.

Advances in Oral Drug Delivery for Regional Targeting in the Gastrointestinal Tract - Influence of Physiological, Pathophysiological and Pharmaceutical Factors.

The oral route is by far the most common route of drug administration in the gastrointestinal tract and can be used for both systemic drug delivery and for treating local gastrointestinal diseases. It is the most preferred route by patients, due to its advantages, such as ease of use, non-invasiveness, and convenience for self-administration. Formulations can also be designed to enhance drug delivery to specific regions in the upper or lower gastrointestinal tract. Despite the clear advantages offered by the oral route, drug delivery can be challenging as the human gastrointestinal tract is complex and displays a number of physiological barriers that affect drug delivery. Among these challenges are poor drug stability, poor drug solubility, and low drug permeability across the mucosal barriers. Attempts to overcome these issues have focused on improved understanding of the physiology of the gastrointestinal tract in both healthy and diseased states. Innovative pharmaceutical approaches have also been explored to improve regional drug targeting in the gastrointestinal tract, including nanoparticulate formulations. This review will discuss the physiological, pathophysiological, and pharmaceutical considerations influencing drug delivery for the oral route of administration, as well as the conventional and novel drug delivery approaches. The translational challenges and development aspects of novel formulations will also be addressed.

Advances in Nanoparticulate Drug Delivery Approaches for Sublingual and Buccal Administration.

The sublingual and buccal routes of administration have significant advantages for both local and systemic drug delivery. They have shown to be an effective alternative to the traditional oral route, especially when fast onset of action is required. Drugs can be rapidly and directly absorbed into the systemic circulation via venous drainage to the superior vena cava. Therefore, they are useful for drugs that undergo high hepatic clearance or degradation in the gastrointestinal tract, and for patients that have swallowing difficulties. Drugs administered via the sublingual and buccal routes are traditionally formulated as solid dosage forms (e.g., tablets, wafers, films, and patches), liquid dosage forms (e.g., sprays and drops), and semi-solid dosage forms (e.g., gels). Conventional dosage forms are commonly affected by physiological factors, which can reduce the contact of the formulation with the mucosa and lead to unpredictable drug absorption. There have been a number of advances in formulation development to improve the retention and absorption of drugs in the buccal and sublingual regions. This review will focus on the physiological aspects that influence buccal and sublingual drug delivery and the advances in nanoparticulate drug delivery approaches for sublingual and buccal administration. The clinical development pipeline with formulations approved and in clinical trials will also be addressed.

Physiological and Pharmaceutical Considerations for Rectal Drug Formulations.

Although the oral route is the most convenient route for drug administration, there are a number of circumstances where this is not possible from either a clinical or pharmaceutical perspective. In these cases, the rectal route may represent a practical alternative and can be used to administer drugs for both local and systemic actions. The environment in the rectum is considered relatively constant and stable and has low enzymatic activity in comparison to other sections of the gastrointestinal tract. In addition, drugs can partially bypass the liver following systemic absorption, which reduces the hepatic first-pass effect. Therefore, rectal drug delivery can provide significant local and systemic levels for various drugs, despite the relatively small surface area of the rectal mucosa. Further development and optimization of rectal drug formulations have led to improvements in drug bioavailability, formulation retention, and drug release kinetics. However, despite the pharmaceutical advances in rectal drug delivery, very few of them have translated to the clinical phase. This review will address the physiological and pharmaceutical considerations influencing rectal drug delivery as well as the conventional and novel drug delivery approaches. The translational challenges and development aspects of novel formulations will also be discussed.

Impact of pharmaceutical care in the improvement of medication adherence and quality of life for COPD patients in Vietnam.

BACKGROUND: Medication adherence is an important factor in the management of chronic obstructive pulmonary disease (COPD). However, the rate of non-adherence to medications is high in COPD and is associated with worsened clinical outcomes and health-related quality of life for patients. OBJECTIVES: Our study aimed to evaluate the impact of a pharmaceutical care program led by pharmacists in the improvement of medication adherence and quality of life for COPD patients in Vietnam. METHODS: A pre- and post-intervention study was conducted over 12 months. Pharmacists provided brief counselling which focused on the role of COPD medications and the importance of adherence. Morisky Medication Adherence Scale was used to evaluate patients' adherence. Quality of life was assessed using the EQ-5D-5L questionnaire and clinical outcomes were evaluated by symptom scores. These outcomes were reassessed at baseline (T0), after 3 months (T1), 6 months (T2) and 12 months (T3). RESULTS: Study participants consisted of 211 COPD patients (mean age: 66.6 ±â€¯8.2 years). The percentage of patients with good adherence significantly increased from 37.4% to 53.2% (p < 0.001) after the program. Mean medication adherence scores improved from 6.7 (T0) to 7.4 (T2) and 7.4 (T3) (p < 0.001). EQ-5D-5L index values also increased from 0.47 (T0) to 0.59 (T3) (p < 0.001). There was no significant change in symptom scores across the duration of the study. CONCLUSIONS: Medication adherence and quality of life of COPD patients improved considerably after implementation of a pharmaceutical care program, thus supporting a vital role for pharmacists alongside physicians in the management of COPD.

Shear stress-induced nuclear shrinkage through activation of Piezo1 channels in epithelial cells.

The cell nucleus responds to mechanical cues with changes in size, morphology and motility. Previous work has shown that external forces couple to nuclei through the cytoskeleton network, but we show here that changes in nuclear shape can be driven solely by calcium levels. Fluid shear stress applied to MDCK cells caused the nuclei to shrink through a Ca2+-dependent signaling pathway. Inhibiting mechanosensitive Piezo1 channels through treatment with GsMTx4 prevented nuclear shrinkage. Piezo1 knockdown also significantly reduced the nuclear shrinkage. Activation of Piezo1 with the agonist Yoda1 caused similar nucleus shrinkage in cells not exposed to shear stress. These results demonstrate that the Piezo1 channel is a key element for transmitting shear force input to nuclei. To ascertain the relative contribution of Ca2+ to cytoskeleton perturbation, we examined F-actin reorganization under shear stress and static conditions, and showed that reorganization of the cytoskeleton is not necessary for nuclear shrinkage. These results emphasize the role of the mechanosensitive channels as primary transducers in force transmission to the nucleus.