Long-term Drug Administration Research Articles

Physically Crosslinked Polymeric Network for Controlled and Mucoadhesive Release of Miconazole for Topical Ocular Delivery

Background: Eudragit L100, filled with miconazole and gelatinous polymeric eye drops, is designed to sustain the drug release and increase ocular effect. Methods: The solvent diffusion technique was used to obtain the polymeric solution. The formulations developed were fully characterized and examined. Results: The optimized drug had a particle size of 71.15 2.3 nm, a zeta potential of approx. 2.57 to 0.76 mV, a polydispersity index of approx. 0.184 and a capture efficiency of 0.10% of 58.049. The prepared efforts showed a fungicidal effect on Candidiasis albicans cultures. Conclusion: The polymeric solution containing the drug-filled with miconazole (MZ) showed an abrupt release in the first hours, followed by the pattern of sustained drug release. A higher cumulative corneal permeability was observed from MZ-containing polymeric solution, which prolonged MZ release in goat eyes. Mucoadhesive liners containing miconazole-loaded Eudragit L100 polymeric solution provide a promising approach to the ocular administration of miconazole (a fungicide) for the treatment of ocular infections requiring long-term drug administration.

The future of metronomic chemotherapy: experimental and computational approaches of drug repurposing.

Metronomic chemotherapy (MC), long-term continuous administration of anticancer drugs, is gaining attention as an alternative to the traditional maximum tolerated dose (MTD) chemotherapy. By combining MC with other treatments, the therapeutic efficacy is enhanced while minimizing toxicity. MC employs multiple mechanisms, making it a versatile approach against various cancers. However, drug resistance limits the long-term effectiveness of MC, necessitating ongoing development of anticancer drugs. Traditional drug discovery is lengthy and costly due to processes like target protein identification, virtual screening, lead optimization, and safety and efficacy evaluations. Drug repurposing (DR), which screens FDA-approved drugs for new uses, is emerging as a cost-effective alternative. Both experimental and computational methods, such as protein binding assays, in vitro cytotoxicity tests, structure-based screening, and several types of association analyses (Similarity-Based, Network-Based, and Target Gene), along with retrospective clinical analyses, are employed for virtual screening. This review covers the mechanisms of MC, its application in various cancers, DR strategies, examples of repurposed drugs, and the associated challenges and future directions.

The combination of hydrogels and rutin-loaded black phosphorus nanosheets treats rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by inflammation, joint pain, and cartilage degradation. The fluctuating nature of RA often necessitates long-term oral administration of treatment drugs, which can unfortunately lead to adverse effects such as gastrointestinal discomfort and hepatic and renal dysfunction. Therefore, a percutaneous local delivery method for the release of inflammatory modulators in arthritic joints represents a promising therapeutic approach for RA. In this study, we have developed a unique and innovative therapeutic platform (named BP-Rut@Gel). This hydrogel was formulated by incorporating the drug Rutin (Rut) into Black phosphorus nanosheets (BP) and subsequently integrating them within a Hyaluronic Acid (HA) and Polyvinyl Alcohol (PVA) matrix to create a composite hydrogel. Notably, Secondly, photothermal therapy (PTT) under Near-Infrared Irradiation (NIR) and anti-inflammatory drugs synergistically worked together to efficiently quell inflammation and enhance therapeutic effectiveness. Additionally, toxicity experiments have revealed that our synthesized black phosphorus nanosheet composite hydrogel possesses excellent biocompatibility and significantly reduces the inflammatory response in RA joints. Given these remarkable properties, our BP-Rut@Gel hydrogel held significant promise and demonstrated immense clinical potential for the treatment of RA.

276 Use of triaxial accelerometers and a machine learning algorithm for behavioral identification to assess the effectiveness of a joint supplement in old domestic cats (Felis catus)

Abstract Degenerative joint disease (DJD) has a 90% prevalence in older cats and adversely affects quality of life1. Long-term administration of non-steroidal anti-inflammatory drugs is usually required but can have adverse effects2. Nutraceuticals have been shown to relieve joint pain in cats without such side effects; however, due to differences in dose rates and formulations there is no consensus as to their efficacy. Most studies have utilized subjective insensitive measures such as veterinary or owner-assessed changes in activity. Accelerometers can provide objective data on cat activity and can identify specific behaviors3.Triaxial accelerometers (ActiGraph, Pensacola, FL) were fitted to the collars of 16 cats (aged 11 to 16 yr; Massey University, Palmerston North, NZ) for 20 wk to assess their activity and behavior. The cats were fed the same diet (Chef: Kraft Heinz Wattie’s Ltd., Hastings, NZ) for 4 wk to collect baseline acceleration data, before being divided into two groups balanced for physical activity. After 4 wk, a blood sample were taken from all of the cats to establish their baseline levels of a range of inflammatory markers (e.g., IL-6, TNFα, INF- γ, SDF-1). The test group (n = 8) then received a joint supplement added to the baseline diet while the control group (n = 8) were fed the diet unsupplemented for 16 wk. The commercial joint supplement contained glucosamine, chondroitin sulphate, and green-lipped mussel (Tandem, Wellington, NZ), at daily doses shown previously to be effective in cats4,5,6. The aim of the work was to assess the efficacy of the joint supplement in maintaining or promoting activity and specific behaviors in the cats. At the end of the period of supplementation a second blood sample was taken and assessed for the same range of inflammatory markers. Overall physical activity was not different between groups at baseline but was greater over the study in the test group compared with the control (P < 0.03). Grooming, as identified by the algorithm, showed a tendency (P = 0.051) to be greater in the test group than the control. These results suggest that the supplement had a positive effect on both overall activity and more specifically on grooming behavior in old cats. However, no differences in the range of inflammatory markers were seen before or after supplementation. While the behavioral measures could indicate the supplement reduced the effects of DJD, further research is required to confirm this.1Cunningham et al (2022) Journal of Feline Medicine and Surgery 24, 962-974. 2Lemetayer and Taylor (2014) Journal of Feline Medicine and Surgery 16, 547-562; 3Smit et al., (2023) Sensors 23, 7165; 4Corbee (2022) Veterinary Medicine and Science 8, 1025–1035; 5Corbee et al. (2013) Journal of Animal Physiology and Animal Nutrition 97, 846–853; 6Lascelles et al. (2010) Journal of Veterinary Internal Medicine, 24, 487–495.

Comparison of the Effect of Auriculotherapy, a Herbal Compound (Aslagh Capsule), and Metformin on the Clinical Symptoms of Polycystic Ovary Syndrome: Randomized Clinical Trial.

Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects women of child-bearing age, with a worldwide prevalence ranging from 6 to 20%. Considering the potential side effects of chemical medications and the need for long-term drug administration, complementary treatments such as acupuncture, auriculotherapy, and herbal medicine have been considered. Hence, this study was designed to compare the effects of auriculotherapy, a herbal component (Aslagh capsule), and metformin on the clinical symptoms of PCOS. This is a randomized controlled clinical trial study, which allocated 24 women, aged 18-43 years old, with oligomenorrhea in PCOs, in a 1:1:1 ratio, to three groups. A decreasing pattern in the duration of the menstrual cycle was observed in all three groups, but this was significant only in the auriculotherapy group. There were no significant differences between the three groups in acne and hirsutism scores. However, there was a significant reduction in excess hair growth and density of hair in the auriculotherapy group compared to the other two groups (P < 0.05). Besides, in the auriculotherapy group, the reduction in thickness of excess hair at the end of the second and third months of treatment were marginally significant compared to the two other groups. Auriculotherapy and Aslagh capsule can be effective in reducing PCOS symptoms, similar to metformin. However, auriculotherapy is more effective than the other treatments in reducing the duration of the menstrual cycle, excess hair growth, and hair density.

Advancements in Soft Robotic Implants for Long-Term Drug Delivery and Tissue Monitoring

Soft robotic implants are a major upgrade in medical devices providing novel means for long-term drug administration and tissue tracking. The eco-friendly biodegradable body-prosthetic will not only be compatible with the human body, but can also mingle completely without inducing foreign-body responses and discomfort. Since these implants provide programmed and localized drug delivery; hence the significance of these sutures could be found in administering the drugs at a specific site and specific interval so as to diminish the side effects and improved therapeutic outcomes. Modern developments of soft robotics implants have improved their design, performance, interaction with biological and other natural materials. Material developments are becoming smarter, where responsive materials in the form of: smart materials, which can react to environmental stimuli and adjust drug delivery rates immediately (and); etc. Moreover, the evolution of microfabrication and nanotechnology also created high precision and less invasive devices, rendering more efficient and well-accepted to patients. These implants are especially valuable for long-term afflictions like diabetes and cancer as they streamline the ongoing, precise delivery of medications. They also have a crucial role in pain management and postoperative care, effectively providing prolonged release of analgesics, and ultimately enhance patient comfort thus contributing to smoother recovery. For tissue monitoring, implantable flexible soft robotic devices with integrated sensors and actuators are able to provide real-time data collection and analysis for the continuous monitoring of vital physiological information, such as cardiovascular health, neural activity, skin conditions (wound healing) etc. This is important, particularly for early detection of complications and receiving timely interventions to optimize patient outcomes. In the future there are a number of intriguing applications that could be developed with these soft robotic implants like personalized medicine and integration with other state-of-the-art medical technologies. Further research and development should/hopefully will address outstanding challenges e.g. technical, regulatory etc to allow more wide-ranging clinical application with consequent transformative impacts on healthcare. Finally, soft robotic implants show great potential to improve drug delivery and tissue monitoring, with continuous development bringing the field closer to better performing medical solutions.

The evaluation of risk factors for prolonged viral shedding during anti-SARS-CoV-2 monoclonal antibodies and long-term administration of antivirals in COVID-19 patients with B-cell lymphoma treated by anti-CD20 antibody

BackgroundThe global impact of the coronavirus disease 2019 (COVID-19) pandemic has resulted in significant morbidity and mortality. Immunocompromised patients, particularly those treated for B-cell lymphoma, have shown an increased risk of persistent infection with SARS-CoV-2 and severe outcomes and mortality. Multi-mutational SARS-CoV-2 variants can arise during the course of such persistent cases of COVID-19. No optimal, decisive strategy is currently available for patients with persistent infection that allows clinicians to sustain viral clearance, determine optimal timing to stop treatment, and prevent virus reactivation. We introduced a novel treatment combining antivirals, neutralizing antibodies, and genomic analysis with frequent monitoring of spike-specific antibody and viral load for immunocompromised patients with persistent COVID-19 infection. The aim of this retrospective study was to report and evaluate the efficacy of our novel treatment for immunocompromised B-cell lymphoma patients with persistent COVID-19 infection.MethodsThis retrospective descriptive analysis had no controls. Patients with B-cell lymphoma previously receiving immunotherapy including anti-CD20 antibodies, diagnosed as having COVID-19 infection, and treated in our hospital after January 2022 were included. We selected anti-SARS-CoV-2 monoclonal antibodies according to subvariants. Every 5 days, viral load was tested by RT-PCR, with antivirals continued until viral shedding was confirmed. Primary outcome was virus elimination. Independent predictors of prolonged viral shedding time were determined by multivariate Cox regression.ResultsForty-four patients were included in this study. Thirty-five patients received rituximab, 19 obinutuzumab, and 26 bendamustine. Median treatment duration was 10 (IQR, 10–20) days; 22 patients received combination antiviral therapy. COVID-19 was severe in 16 patients, and critical in 2. All patients survived, with viral shedding confirmed at median 28 (IQR, 19–38) days. Bendamustine use or within 1 year of last treatment for B-cell lymphoma, and multiple treatment lines for B-cell lymphoma significantly prolonged time to viral shedding.ConclusionsAmong 44 consecutive patients treated, anti-SARS-CoV-2 monoclonal antibodies and long-term administration of antiviral drugs, switching, and combination therapy resulted in virus elimination and 100% survival. Bendamustine use, within 1 year of last treatment for B-cell lymphoma, and multiple treatment lines for B-cell lymphoma were the significant independent predictors of prolonged viral shedding time.

Chronic pyogenic spondylitis in patients with spinal gout: a case series and literature review

Background. Spinal gout is a rare and poorly described group of noninfectious inflammatory spinal lesions characterized by the deposition of monosodium urate crystals in the epidural space, paravertebral soft tissues, and by facet joints damage. There is no systematized data on the course of infectious spondylitis and spinal gout in the literature. The aim of the study — to present long-term outcomes of surgical treatment of chronic pyogenic spondylitis in patients with spinal gout and systematize the literature data on the issue. Methods. The clinical part of the study included 6 consecutively operated patients in the period from 2018 to 2021. The diagnosis of spinal gout and chronic pyogenic spondylitis was verified according to the results of histologic and bacteriologic studies of surgical material. Catamnesis accounted for at least 12 months. We studied the peculiarities of clinical and laboratory, radiological and histologic manifestations of the disease. Literature data systematization was carried out in the databases PubMed, Google Scholar, eLIBRARY from 2013 to 2023. Inclusion criteria: level of evidence II B-IV, catamnesis more or equal to 6 months, information on diagnostic and treatment measures. Results. The average age of the patients was 55±9 years. The duration of the diagnostic pause was 8±5 years. Multisegmented lesions of the lumbar (n = 6) spine prevailed. According to the classification of Pola E. et al. (2017) the following types of spondylitis were identified: B.3 (n = 1), C.1 (n = 1), C.3 (n = 2) and C.4 (n = 2). The clinical manifestation was dominated by chronic back pain with an intensity of 6,1±1,4 VAS scores. Neurologic disorders of the lower extremities and pelvic (ASIA scale) corresponded to types B (n = 1) and C (n = 4). The type of surgery: three-column reconstruction through combined approach in 2 cases and isolated anterior column reconstruction in 2 cases, 360° fusion in 1 case, and debridement of the epidural space and anterior column through posterior approach in 1 case. The follow-up results show the absence of recurrence of spondylitis in 4 cases, in 2 patients there were postoperative complications that required revision, after which no recurrence of spondylitis was noted. We selected 17 publications for literature review. Conclusion. The combination of chronic pyogenic spondylitis and spinal gout is a rare and poorly described pathology in the literature. Long therapeutic pause, chronic character of vertebrogenic pain syndrome in combination with increased uric acid level and formation of tophi of vertebral localization are distinctive features of the disease. Neurologic disorders with the combination of spondylitis and gout result from stenosis of the spinal canal due to two factors — epidural abscesses and tophi. Achieving local control of the combined pathology is possible with a combination of surgical intervention and long-term administration of hypouricemic drugs.

Long-Term Pharmacokinetic Follow-Up of Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer.

This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients.

Long-term toxicity evaluation of aristolochic acid-IIIa in mice

Aristolochic acid (AA)-IIIa is an AA analog present in Aristolochiaceae plants. To evaluate the chronic toxicity of AA-IIIa, mice were intragastrically administered with media control, 1 mg/kg AA-IIIa, and 10 mg/kg AA-IIIa, and designated as the control (CTL), AA-IIIa low dose (AA-IIIa-L), and AA-IIIa high dose (AA-IIIa-H) groups, respectively. AA-IIIa was administered three times a week, every other day, for 24 weeks (24-week time point). Thereafter, some mice were sacrificed immediately, while others were sacrificed 29 or 50 weeks after AA-IIIa withdrawal (53- or 74-week time point). Serum and organs were collected for biochemical and pathological analyses, respectively. Whole-genome sequencing was performed on the kidney, liver, and stomach tissues of AA-IIIa-treated mice for single-nucleotide polymorphism (SNP) detection. AA-IIIa-H mice died at 66 weeks, and the remaining mice showed moribund conditions at the 69 weeks. AA-IIIa induced minor kidney tubule injury, fibroblast hyperplasia, and forestomach carcinoma in mice. Bladder, intestine, liver, heart, spleen, lung, and testis tissues were not pathologically altered by AA-IIIa. In addition, AA-IIIa increased the C:G > A:T mutation in the kidney; however, no SNP mutation changes were observed in the liver and forestomach tissues of AA-IIIa-H mice at the 24-week time point compared with control mice. Therefore, we suspect that AA-IIIa is potentially mutagenic for mice after overdose and long-term administration. On the other hand, the forestomach is a unique organ in mice, but it does not exist in humans; thus, we hypothesize that the stomach toxicity induced by AA-IIIa is not a suitable reference for toxicological evaluation in humans. We recommend that Aristolochiaceae plants containing AA-IIIa should be properly supervised, and overdosing and long-term administration of drugs containing AA-IIIa should be avoided.

Reactive Oxygen Species-Responsive Dual Anti-Inflammatory and Antioxidative Nanoparticles for Anterior Uveitis.

Anterior uveitis (AU) is an immune-mediated inflammatory disease that results in iritis, cyclitis, glaucoma, cataracts, and even a loss of vision. The frequent and long-term administration of corticosteroid drugs is limited in the clinic owing to the side effects and patient noncompliance with the drugs. Therefore, specifically delivering drugs to inflammatory anterior segment tissues and reducing the topical application dosage of the drug are still a challenge. Here, we developed dual dexamethasone (Dex) and curcumin (Cur)-loaded reactive oxygen species (ROS)-responsive nanoparticles (CPDC NPs) to treat anterior uveitis. The CPDC NPs demonstrated both anti-inflammatory and antioxidative effects, owing to their therapeutic characteristics of dexamethasone and curcumin, respectively. The CPDC NPs could effectively release dexamethasone and curcumin in the oxidizing physiological environment of the inflammation tissue. The CPDC NPs can effectively internalize by activated macrophage cells, subsequently suppressing the proinflammatory factor expression. Moreover, the CPDC NPs can inhibit ROS and inflammation via nuclear transcription factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway activation. In an endotoxin-induced uveitis rabbit model, the CPDC NPs show a therapeutic effect that is better than that of either free drugs or commercial eye drops. Importantly, the CPDC NPs with a lower dexamethasone dosage could reduce the side effects significantly. Taken together, we believe that the dual-drug-loaded ROS-responsive NPs could effectively target and inhibit inflammation and have the potential for anterior uveitis treatment in clinical practice.

Comparison of a brand-name drug and its generic drugs - Impact of anti-human immunodeficiency virus drug exposure on the intestinal epithelial barrier

The use of unapproved anti-human immunodeficiency virus (HIV) drugs for its treatment and prevention has recently increased in Japan. Our research group investigated generic drugs of the Truvada combination tablet (TVD) that have not been approved in Japan, and reported differences in the pharmaceutical properties of their formulations. We also demonstrated that the pharmaceutical excipients in generic drugs may differ from those in TVD, and showed that some pharmaceutical excipients may affect epithelial cell barrier function. The present study investigated differences in the effects of TVD and its generic drugs (Generic A and Generic B) on epithelial cell barrier function. No significant differences were observed in epithelial cell barrier function following exposure to TVD, Generic A, and Generic B. However, significant increases in the mRNA levels of ABCB1 and Occludin, which regulate the epithelial cell barrier, were detected following exposure to Generic B. Therefore, the administration of Generic B for a longer duration or at a higher concentration may lead to changes in epithelial barrier function. Since the treatment and prevention of HIV requires the long-term (chronic) administration of drugs, the drugs used may change, such as from a brand-name drug to a generic drug and also from one generic drug to another. The present results suggest that the effects of brand-name and generic drugs, such as on intestinal epithelial barrier function, may differ with changes in the drugs being administered.

Elimination of transmission of onchocerciasis (river blindness) with long-term ivermectin mass drug administration with or without vector control in sub-Saharan Africa: a systematic review and meta-analysis

WHO has proposed elimination of transmission of onchocerciasis (river blindness) by 2030. More than 99% of cases of onchocerciasis are in sub-Saharan Africa. Vector control and mass drug administration of ivermectin have been the main interventions for many years, with varying success. We aimed to identify factors associated with elimination of onchocerciasis transmission in sub-Saharan Africa. For this systematic review and meta-analysis we searched for published articles reporting epidemiological or entomological assessments of onchocerciasis transmission status in sub-Saharan Africa, with or without vector control. We searched MEDLINE, PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, African Index Medicus, and Google Scholar databases for all articles published from database inception to Aug 19, 2023, without language restrictions. The search terms used were "onchocerciasis" AND "ivermectin" AND "mass drug administration". The three inclusion criteria were (1) focus or foci located in Africa, (2) reporting of elimination of transmission or at least 10 years of ivermectin mass drug administration in the focus or foci, and (3) inclusion of at least one of the following assessments: microfilarial prevalence, nodule prevalence, Ov16 antibody seroprevalence, and blackfly infectivity prevalence. Epidemiological modelling studies and reviews were excluded. Four reviewers (NM, AJ, AM, and TNK) extracted data in duplicate from the full-text articles using a data extraction tool developed in Excel with columns recording the data of interest to be extracted, and a column where important comments for each study could be highlighted. We did not request any individual-level data from authors. Foci were classified as achieving elimination of transmission, being close to elimination of transmission, or with ongoing transmission. We used mixed-effects meta-regression models to identify factors associated with transmission status. This study is registered in PROSPERO, CRD42022338986. Of 1525 articles screened after the removal of duplicates, 75 provided 282 records from 238 distinct foci in 19 (70%) of the 27 onchocerciasis-endemic countries in sub-Saharan Africa. Elimination of transmission was reported in 24 (9%) records, being close to elimination of transmission in 86 (30%) records, and ongoing transmission in 172 (61%) records. I2 was 83·3% (95% CI 79·7 to 86·3). Records reporting 10 or more years of continuous mass drug administration with 80% or more therapeutic coverage of the eligible population yielded significantly higher odds of achieving elimination of transmission (log-odds 8·5 [95% CI 3·5 to 13·5]) or elimination and being close to elimination of transmission (42·4 [18·7 to 66·1]) than those with no years achieving 80% coverage or more. Reporting 15-19 years of ivermectin mass drug administration (22·7 [17·2 to 28·2]) and biannual treatment (43·3 [27·2 to 59·3]) were positively associated with elimination and being close to elimination of transmission compared with less than 15 years and no biannual mass drug administration, respectively. Having had vector control without vector elimination (-42·8 [-59·1 to -26·5]) and baseline holoendemicity (-41·97 [-60·6 to -23·2]) were associated with increased risk of ongoing transmission compared with no vector control and hypoendemicity, respectively. Blackfly disappearance due to vector control or environmental change contributed to elimination of transmission. Mass drug administration duration, frequency, and coverage; baseline endemicity; and vector elimination or disappearance are important determinants of elimination of onchocerciasis transmission in sub-Saharan Africa. Our findings underscore the importance of improving and sustaining high therapeutic coverage and increasing treatment frequency if countries are to achieve elimination of onchocerciasis transmission. The Bill & Melinda Gates Foundation and Neglected Tropical Diseases Modelling Consortium, UK Medical Research Council, and Global Health EDCTP3 Joint Undertaking. For the Swahili, French, Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Long-Term Constant Subcutaneous Drug Administration.

In this chapter, a long-term drug delivery system for preclinical therapeutic research is introduced. By using a subcutaneously implanted ALZET® Osmotic Pumps osmotic pump, continuous zero-order delivery of drugs under investigation that need repeated oral or intravenous dosing is realizable. Compared to traditional delivery systems, implanted osmotic pumps present several advantages, such as that no external connections or researcher intervention is required during infusion and that it is possible to save time by eliminating the need for frequent animal handling and repetitive injection schedules. Most importantly, a stable peripheral concentration of a drug can be obtained using this constant drug delivery system, which would benefit researchers in verifying the efficiency of anti-rheumatoid drugs and establishing safety profiles in preclinical studies.

Platelet membrane encapsulated curcumin nanomaterial-mediated specific thrombolysis and anti-thrombotic treatment among pregnant women.

The current treatment for venous thrombosis during pregnancy is ineffective, primarily, due to the unique physiology of pregnant women. Most clinical medications have fetal side effects when they circulate in the body. We first synthesized nanomaterials (Cur-PFP@PC) using poly lactic-co-glycolic acid (PLGA) as the base material, with curcumin (Cur) and perfluoropentane (PFP) as core components. Subsequently, we encapsulated Cur-PFP@PC into the platelet membrane to synthesize P-Cur-PFP@PC. Under ultrasound guidance, in combination with low-intensity focused ultrasound (LIFU), PFP underwent a phase change, resulting in thrombolysis. The generated microbubbles enhanced the signal impact of ultrasound, and P-Cur-PFP@PC showed better performance than Cur-PFP@PC. P-Cur-PFP@PC can target thrombosis treatment, achieve visually and precisely controlled drug release, and repair damaged blood vessels, thus avoiding the adverse effects associated with traditional long-term drug administration.

A ROS-responsive microsphere capsule encapsulated with NADPH oxidase 4 inhibitor ameliorates macrophage inflammation and ferroptosis

Inflammatory macrophages within the synovium play a pivotal role in the progression of arthritis inflammation. Effective drug therapy targeting inflammatory macrophages has long been a goal for clinicians and researchers. The standard approach for treating osteoarthritis (OA) involves systemic treatment and local injection. However, the high incidence of side effects associated with long-term drug administration increases the risk of complications in patients. Additionally, the rapid clearance of the joint cavity poses a biological barrier to the therapeutic effect. NADPH oxidase 4 (NOX4) is an enzyme protein regulating the cellular redox state by generating reactive oxygen species (ROS) within the cell. In this study, we designed and fabricated a hydrogel microsphere consisting of methyl methacrylate (MMA) and polyvinyl acetate (PVA) as the outer layer structure. We then loaded GLX351322 (GLX), a novel selective NOX4 inhibitor, into hydrogel microspheres through self-assembly with the compound polyethylene glycol ketone mercaptan (mPEG-TK) containing a disulfide bond, forming nanoparticles (mPEG-TK-GLX), thus creating a two-layer drug-loaded microspheres capsule with ROS-responsive and slow-releasing capabilities. Our results demonstrate that mPEG-TK-GLX@PVA-MMA effectively suppressed TBHP-induced inflammation, ROS production, and ferroptosis, indicating a promising curative strategy for OA and other inflammatory diseases in the future.

Toxicity study of compound granules of Hedyotis diffusa: Acute toxicity and long-term toxicity

Ethnopharmacological relevanceThe clinical efficacy of the hospital preparation compound granules of Hedyotis diffusa (CGHD), which is composed of Hedyotis diffusa Willd, Smilax china L., Solanum lyratum Thunb., has accumulated a good reputation over the past decades. However, because it is a hospital preparation, few researchers have paid attention to it, resulting in a lack of systematic basic research studies. Thus, it is not clear whether there are safety concerns that restrict its clinical application, and toxicological evaluation of CGHD is needed. Aim of the studyThe aim of this study was to evaluate the safety of CGHD by conducting acute toxicity and long-term toxicity experiments, with the objective of providing evidence for its clinical safety and a theoretical foundation for its clinical application. Materials and methodsKM mice were selected for the acute toxicity experiment and were administered water or CGHD-E 3 times within 24 h. The reactions of the animals to CGHD treatment were observed and recorded within 1 h after administration and then once a day for 14 consecutive days. SD rats were selected to conduct the long-term toxicity experiment. The drug-treated groups were administered different doses of CGHD-E, which were equivalent to 10 times, 20 times and 50 times the clinical dose in humans. The rats were administered the drug for 28 consecutive days. After 28 days, the animals were sacrificed, and routine blood tests, blood coagulation function analysis, liver and kidney function tests, and glycolipid metabolism related tests were conducted. The major organs of the rats were collected to calculate organ coefficients and perform hematoxylin-eosin (HE) staining. ResultsIn the CGHD-E acute toxicity experiment, the drug-treated groups did not show adverse reactions or poisoning symptoms, and the maximum tolerated dose of CGHD-E in mice was greater than 45.072 g/kg. In the long-term toxicity experiment, drug-treated rats generally exhibited a good condition, but continuous administration decreased on body weight and food intake, especially in male rats. Coagulation function alterations and the impact on the liver during long-term drug administration were also assessed, which should be emphasized in clinical applications. No significant toxic effects were observed according to routine blood tests or test of liver and kidney function, glucose and lipid metabolism, or ion metabolism. ConclusionsThe results of this study showed that CGHD was nontoxic or had low toxicity, providing not only a scientific basis for its clinical application, determining the appropriate clinical dose and monitoring clinical toxicity but also theoretical support for subsequent clinical drug trials.

Detection of Aspergillus Sp Fungus in Tuberculosis Patients with A Treatment Length of 2 Months using the Polymerace Chain Reaction (Pcr) Method

This study aims to detect the presence or absence of the Aspergillus sp fungus in Tuberculosis Patients within a 2 month treatment period. This research was carried out in the Microbiology Laboratory at Hasanuddin University Teaching Hospital. Laboratory methods. Samples were obtained from the Tabaringan and Pattingaloang Community Health Centers in Makassar City. Then testing was carried out using culture techniques and polymerace chain reaction techniques. The research results showed that by using the culture method from 30 samples, 9 samples obtained growing media, for 2 samples it was suspected that Aspergillus sp fungus was growing. Then for the polymerace chain reaction (PCR) method, from 30 samples the presence of Aspergillus sp fungus was detected, 4 samples using ASAP primers, then carried out again using ASPU primers (ASPU+Af3r, ASPU+Ni1r, ASPU+Fl2r) which resulted in 1 Aspergillus niger sample. From the results of this research, it can be concluded that the factor that causes the growth of fungus is the long-term administration of anti-tuberculosis drugs which only suppress bacteria from pulmonary tuberculosis.

Intravitreal injectable hydrogel rods with long-acting bevacizumab delivery to the retina.

Retinal vascular diseases such as neovascular age-related macular degeneration (nAMD) are the leading cause of blindness worldwide. They can be treated with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents by inhibiting VEGF which is a major agent of abnormal blood vessel growth. However, because of drug's short half-life, clinical treatment often requires monthly repeated intravitreal injections, causing treatment burden and undertreatment. Among various kinds of drug carriers, in situ forming hydrogels have been studied as potential intravitreal drug carriers for the high drug loading, easy injection, controlled drug release, and protection of encapsulated drugs from the environment. However, gelation time, crosslinking degree, and drug release patterns following injection of a liquid that will be subsequently gelled in situ are susceptible to be hindered by dilution of the hydrogel precursor solution with body fluids (e.g., blood or vitreous). Here, we report an injectable pre-crosslinked hydrogel rod to overcome the limitations of in situ forming hydrogels and to extend intravitreal half-life of anti-VEGF for reducing intraocular injection frequency. Hydrogel rods can be simply prepared using in situ forming hydrogels, and injectable using a designed rod injector. The adjustable crosslinking degree of hydrogel rods easily controlled bevacizumab release profiles in a sustained manner. Compared with in situ forming hydrogels, hydrogel rods effectively reduced initial burst release, and showed sustained release with long-term drug efficacy in vitro. From the 4-month in vivo pharmacokinetic analysis, following the intravitreal injection of hydrogel rods, the half-life of bevacizumab in the vitreous and retina was significantly extended, and drug elimination to aqueous humor was effectively reduced. Finally, intraocular stability, degradation, and inflammatory response of hydrogel rods were evaluated. We expect that the hydrogel rod can be a potential drug delivery system for the treatment of nAMD and other conditions that need long-term and local sustained drug administration. STATEMENT OF SIGNIFICANCE: Herein, we report an injectable pre-crosslinked hydrogel rod based on an in situ forming hydrogel to achieve intravitreal long-acting anti-VEGF delivery to reduce injection frequency and improve the long-term visual outcomes of patients with retinal vascular diseases. Hydrogel rods were readily prepared using removable molds and injected using customized injectors. Compared to the in situ forming hydrogel, hydrogel rods showed significantly reduced initial burst release, controllable release profiles for several months, physical stability, and a long-acting anti-angiogenic effect. Animal studies demonstrated that the hydrogel rods dramatically prolonged the intraocular drug half-life while significantly reducing drug elimination for up to four months. Moreover, the biodegradability and safety of the hydrogel rods suggest their suitability as an advanced intravitreal DDS for treating retinal vascular diseases.

Role of Potassium-competitive Acid Blockers in the Treatment of Gastric Acid-related Disorders

Owing to their superior pharmacokinetic and pharmacodynamic profiles, potassium-competitive acid blockers (P-CABs) score over proton pump inhibitors (PPIs) in the treatment of gastric acid-related disorders and may provide clinical benefit in the management of these conditions. Previous studies have compared P-CABs with PPIs for treatment of gastric acid-related disorders, and current data show that P-CABs are non-inferior to PPIs in the treatment of erosive esophagitis and as maintenance therapy. P-CABs are useful for effective healing and as maintenance medications in patients with severe esophagitis. These drugs also aid with healing of peptic ulcers and artificial ulcers secondary to gastric endoscopic submucosal dissection (ESD). Few studies have discussed prevention of delayed ulcer bleeding after gastric ESD and ulcers associated with long-term nonsteroidal anti-inflammatory drug administration. Well-controlled, large-scale prospective studies are warranted in future to compare P-CABs with PPIs.