Role of prescribed medication in the development of iron deficiency anaemia in adults-a case-control study.

OBJECTIVE: To estimate the strength of association between exposure to selected classes of prescribed medications and the risk of developing iron deficiency anaemia (IDA), specifically considering oral anticoagulants (OACs), antidepressants, antiplatelet agents, proton pump inhibitors (PPIs) and non-steroidal anti-inflammatories. DESIGN: A case-control study involving the analysis of community repeat prescriptions among subjects referred with IDA, and unmatched controls referred as gastroenterology fast-tracks for other indications. Multivariable logistic regression modelling was used to calculate ORs for the association between IDA presentation and each medication class, adjusted for age, sex and coprescribing. For those classes showing significance, it was also used to calculate risk differences between those in the IDA group with or without haemorrhagic lesions on investigation. RESULTS: A total of 1210 cases were analysed-409 in the IDA group, and 801 in the control group. Significant associations were identified between presentation with IDA and long-term exposure to PPIs (OR 3.29, 95% CI: 2.47 to 4.41, p<0.001) and to OACs (OR 2.04, 95% CI: 1.29 to 3.24, p=0.002). IDA was not associated with long-term exposure to any of the other three drug classes. In contrast to the relationship with PPIs, the association with OACs was primarily in the IDA sub-group with haemorrhagic lesions. CONCLUSION: Long-term exposure to PPIs and OACs are independently associated with the risk of developing IDA. There are grounds for considering that these associations may be causal, though the underlying mechanisms probably differ.

A Randomized Control Trial of Dexketoprofen/Vitamin B (Thiamine, Pyridoxine and Cyanocobalamin) Fixed-Dose Combination in Post-Traumatic Grade I-II Cervical Sprains.

BACKGROUND: Musculoskeletal disorders are an important cause of work absence. Clinical practice guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) for grade I-II cervical sprains. The combination of thiamine + pyridoxine + cyanocobalamin vitamins has been used, alone and in combination with NSAIDs, for pain and inflammation in musculoskeletal disorders. OBJECTIVE: The objective of this study was to demonstrate the analgesic synergy of dexketoprofen, and the combination of vitamins thiamine + pyridoxine + cyanocobalamin in a fixed-dose combination (FDC) for the treatment of acute pain caused by grade I-II cervical sprains. METHODS: We conducted a multicentre, prospective, randomized, double-blind, phase IIIb clinical study comparing two treatment groups: (1) dexketoprofen 25 mg/vitamin B (thiamine 100 mg, pyridoxine 50 mg and cyanocobalamin 0.50 mg) in an FDC (two or more active ingredients combined in a single dosage form) versus (2) dexketoprofen 25 mg monotherapy (single drug to treat a particular disease), one capsule or tablet orally, every 8 h for 7 days. Final mean, average change, and percentage change in pain perception (measured using a visual analogue scale [VAS]) were compared with baseline between groups. A p value < 0.05 was considered statistically significant. Analyses were conducted using SPSS software, v.29.0. RESULTS: A statistically significant reduction in pain intensity was observed from the third day of treatment with the FDC compared with monotherapy (- 3.1 ± - 1.5 and - 2.6 ± - 1.1 cm, respectively) measured using the VAS (p = 0.011). Regarding the degree of disability, using the Northwick Park Neck Pain Questionnaire (NPQ), statistical difference was observed for the final measurement (7.5%, interquartile range [IQR] 2.5, 10.5; vs. 7.9%, IQR 5.0, 13.8; p = 0.028). A lower proportion of adverse events was reported when using the FDC. CONCLUSIONS: The FDC of dexketoprofen/thiamine + pyridoxine + cyanocobalamin vitamins demonstrated superior efficacy and a better safety profile compared with dexketoprofen monotherapy for pain treatment in patients with grade I-II cervical sprains. CLINICAL TRIALS REGISTRATION: NCT05001555, registered 29 July 2021 ( https://clinicaltrials.gov/study/NCT05001555 ).

Intravenous ibuprofen versus ketorolac for perioperative pain control in open abdominal hysterectomy: a randomized controlled trial.

BACKGROUND: We aimed to compare the analgesic effects of intravenous ibuprofen to ketorolac after open abdominal hysterectomy. METHODS: This randomized double-blinded controlled trial included adult women scheduled for elective open abdominal hysterectomy. Participants were randomized to receive either 30 mg ketorolac (n = 50) or 800 mg ibuprofen (n = 50) preoperatively, then every 8 h postoperatively for 24 h. All participants received paracetamol 1 gm/6 h. Rescue analgesic was given if the visual analogue scale (VAS) for pain assessment was > 3. The primary outcome was the mean postoperative dynamic VAS during the first 24 h. Secondary outcomes were static VAS, intraoperative fentanyl consumption, postoperative morphine consumption, time to independent movement, and patient's satisfaction. RESULTS: Forty-six patients in the ibuprofen group and fifty patients in the ketorolac group were analyzed. The 24-h dynamic and static VAS were similar in the two groups. The median (quartiles) dynamic VAS was 1.1 (0.9, 1.9) in the ibuprofen group versus 1.0 (0.7, 1.3) in the ketorolac group, P-value = 0.116; and the median (quartiles) static VAS was 0.9 (0.6, 1.3) in the ibuprofen group versus 0.7 (0.4, 1.1) in the ketorolac group, P-value = 0.113. The intra- and postoperative analgesic requirements were also similar in the two groups. However, patient satisfaction was slightly higher in the ketorolac group than that in the ibuprofen group (median [quartiles]: 6 [5, 7] versus 5 [4, 7], respectively), P-value: 0.009. CONCLUSION: The two drugs, intravenous ibuprofen and ketorolac produced similar analgesic profile in patients undergoing open abdominal hysterectomy receiving multimodal analgesic regimen. NCT05610384, Date of registration: 09/11/2022 CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05610384. https://clinicaltrials.gov/ct2/show/NCT05610384.

Pharmacokinetics and Bioequivalence of Apremilast Tablets in Chinese Healthy Subjects Under Fasting and Postprandial States.

Objective: This study compared the pharmacokinetics, safety and bioequivalence (BE) of generic and original apremilast tablets in healthy Chinese subjects under fasting and postprandial conditions, providing sufficient evidence for abbreviated new drug application. Methods: A randomized, open-label, two-formulation, single-dose, two-period crossover pharmacokinetic study was performed. Thirty-two eligible healthy Chinese subjects were enrolled in fasting and postprandial studies, respectively. In each trial, subjects received a single 30-mg dose of the test or reference apremilast tablet, followed by a 7-day washout interval between periods. Serial blood samples were obtained for up to 48 h post-intake in each period, and the plasma concentrations of apremilast were determined by a validated method. The primary pharmacokinetic (PK) parameters, including the maximum plasma concentration (Cmax), the areas under the plasma concentration-time curve (AUC0-t, AUC0-∞), were calculated using the non-compartmental method. The geometric mean ratios of the two formulations and the corresponding 90% confidence intervals (CIs) were acquired for bioequivalence analysis. The safety of both formulations was also evaluated. Results: Under fasting and postprandial states, the PK parameters of the test drug were similar to those of the reference drug. The 90% CIs of the geometric mean ratios of the test to reference formulations were 94.09-103.44% for Cmax, 94.05-103.51% for AUC0-t, and 94.56-103.86% for AUC0-∞ under fasting conditions, and 99.18-112.48% for Cmax, 98.79-106.02% for AUC0-t, and 98.95-105.89% for AUC0-∞ under postprandial conditions, all of which were within the bioequivalence range of 80.00-125.00%. Both formulations were well tolerated, and no serious adverse events occurred during the study. Conclusion: The trial confirmed that the PK parameters of the generic and original apremilast tablets were bioequivalent in healthy Chinese subjects under fasting and postprandial states, which met the predetermined regulatory standards. Both formulations were safe and well tolerated. Clinical Trial Registration: chinaDrugtrials.org.cn, identifier CTR20191056 (July 30, 2019); chictr.org.cn, identifier ChiCTR2300076806 (October 19, 2023).

Mucoadhesive Mesalamine Prodrug Nanoassemblies to Target Intestinal Macrophages for the Treatment of Inflammatory Bowel Disease.

While mesalamine, a 5-aminosalicylic acid (5-ASA), is pivotal in the management of inflammatory bowel disease (IBD) through both step-up and top-down approaches in clinical settings, its widespread utilization is limited by low bioavailability at the desired site of action due to rapid and extensive absorption in the upper gastrointestinal (GI) tract. Addressing mesalamine's pharmacokinetic challenges, here, we introduce nanoassemblies composed exclusively of a mesalamine prodrug that pairs 5-ASA with a mucoadhesive and cathepsin B-cleavable peptide. In an IBD model, orally administered nanoassemblies demonstrate enhanced accumulation and sustained retention in the GI tract due to their mucoadhesive properties and the epithelial enhanced permeability and retention (eEPR) effect. This retention enables the efficient uptake by intestinal pro-inflammatory macrophages expressing high cathepsin B, triggering a burst release of the 5-ASA. This cascade fosters the polarization toward an M2 macrophage phenotype, diminishes inflammatory responses, and simultaneously facilitates the delivery of active agents to adjacent epithelial cells. Therefore, the nanoassemblies show outstanding therapeutic efficacy in inhibiting local inflammation and contribute to suppressing systemic inflammation by restoring damaged intestinal barriers. Collectively, this study highlights the promising role of the prodrug nanoassemblies in enhancing targeted drug delivery, potentially broadening the use of mesalamine in managing IBD.

Self-Assembled Multilayer-Modified Needles Simulate Acupuncture and Diclofenac Sodium Delivery for Rheumatoid Arthritis.

A novel therapeutic approach combining acupuncture and diclofenac sodium (DS) administration was established for the potential treatment for rheumatoid arthritis (RA). DS is a commonly used anti-inflammatory and analgesic drug but has short duration and adverse effects. Acupoints are critical linkages in the meridian system and are potential candidates for drug delivery. Herein, we fabricated a DS-loaded multilayer-modified acupuncture needle (DS-MMAN) and investigated its capacity for inhibiting RA. This DS-MMAN possesses sustained release properties and in vitro anti-inflammatory effects. Experimental results showed that the DS-MMAN with microdoses can enhance analgesia and efficiently relieve joint swelling compared to the oral or intra-articular administration of DS with gram-level doses. Moreover, the combination of acupoint and DS exerts a synergistic improvement in inflammation and joint damage. Cytokine and T cell analyses in the serum indicated that the application of DS-MMAN suppressed the levels of pro-inflammatory factors and increased the levels of anti-inflammatory factors. Furthermore, the acupoint administration via DS-MMAN could decrease the accumulation of DS in the liver and kidneys, which may express better therapeutic efficiency and low toxicity. The present study demonstrated that the acupuncture needle has the potential to build a bridge between acupuncture and medication, which would be a promising alternative to the combination of traditional and modern medicine.

Exploring potential neuroimaging biomarkers for the response to non-steroidal anti-inflammatory drugs in episodic migraine.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are considered first-line medications for acute migraine attacks. However, the response exhibits considerable variability among individuals. Thus, this study aimed to explore a machine learning model based on the percentage of amplitude oscillations (PerAF) and gray matter volume (GMV) to predict the response to NSAIDs in migraine treatment. METHODS: Propensity score matching was adopted to match patients having migraine with response and nonresponse to NSAIDs, ensuring consistency in clinical characteristics and migraine-related features. Multimodal magnetic resonance imaging was employed to extract PerAF and GMV, followed by feature selection using the least absolute shrinkage and selection operator regression and recursive feature elimination algorithms. Multiple predictive models were constructed and the final model with the smallest predictive residuals was chosen. The model performance was evaluated using the area under the receiver operating characteristic (ROCAUC) curve, area under the precision-recall curve (PRAUC), balance accuracy (BACC), sensitivity, F1 score, positive predictive value (PPV), and negative predictive value (NPV). External validation was performed using a public database. Then, correlation analysis was performed between the neuroimaging predictors and clinical features in migraine. RESULTS: One hundred eighteen patients with migraine (59 responders and 59 non-responders) were enrolled. Six features (PerAF of left insula and left transverse temporal gyrus; and GMV of right superior frontal gyrus, left postcentral gyrus, right postcentral gyrus, and left precuneus) were observed. The random forest model with the lowest predictive residuals was selected and model metrics (ROCAUC, PRAUC, BACC, sensitivity, F1 score, PPV, and NPV) in the training and testing groups were 0.982, 0.983, 0.927, 0.976, 0.930, 0.889, and 0.973; and 0.711, 0.648, 0.639, 0.667,0.649, 0.632, and 0.647, respectively. The model metrics of external validation were 0.631, 0.651, 0.611, 0.808, 0.656, 0.553, and 0.706. Additionally, a significant positive correlation was found between the GMV of the left precuneus and attack time in non-responders. CONCLUSIONS: Our findings suggest the potential of multimodal neuroimaging features in predicting the efficacy of NSAIDs in migraine treatment and provide novel insights into the neural mechanisms underlying migraine and its optimized treatment strategy.

[Current challenges for therapy of comorbid patients: a new look at celecoxib. A review].

The use of non-steroidal anti-inflammatory drugs (NSAIDs) for a wide range of diseases is increasing, in part due to an increasing elderly population. Elderly patients are more vulnerable to adverse drug reactions, including side effects and adverse effects of drug-drug interactions, often occurring in this category of patients due to multimorbidity and polypharmacy. One of the most popular NSAIDs in the world is celecoxib. It is a selective cyclooxygenase (COX)-2 inhibitor with 375 times more COX-2 inhibitory activity than COX-1. As a result, celecoxib has a better gastrointestinal tract safety profile than non-selective NSAIDs. Gastrointestinal tolerance is an essential factor that physicians should consider when selecting NSAIDs for elderly patients. Celecoxib can be used in a wide range of diseases of the musculoskeletal system and rheumatological diseases, for the treatment of acute pain in women with primary dysmenorrhea, etc. It is also increasingly used as part of a multimodal perioperative analgesia regimen. There is strong evidence that COX-2 is actively involved in the pathogenesis of ischemic brain damage, as well as in the development and progression of neurodegenerative diseases, such as Alzheimer's disease. NSAIDs are first-line therapy in the treatment of acute migraine attacks. Celecoxib is well tolerated in patients with risk factors for NSAID-associated nephropathy. It does not decrease the glomerular filtration rate in elderly patients and patients with chronic renal failure. Many meta-analyses and epidemiological studies have not confirmed the increased risk of cardiovascular events reported in previous clinical studies and have not shown an increased risk of cardiovascular events with celecoxib, irrespective of dose. COX-2 activation is one of the key factors contributing to obesity-related inflammation. Specific inhibition of COX-2 by celecoxib increases insulin sensitivity in overweight or obese patients. Combination therapies may be a promising new area of treatment for obesity and diabetes.

Pharmacologic interventions for primary glenohumeral osteoarthritis.

ABSTRACT: Primary glenohumeral osteoarthritis is a multifactorial condition with a complex cause that affects patients across different age groups, impairing physiologic and psychologic well-being, and substantially reducing patient quality of life and overall productivity. To effectively manage this condition, healthcare providers need to be well informed about treatment guidelines, as well as the available therapeutic options and the evidence supporting their use. Nonsurgical interventions should be regarded as the primary treatment option, particularly for patients in the initial phases of this condition. No conclusive guidelines exist for treating young and active patients, and the literature lacks high-quality data to evaluate the efficacy, safety, and long-term consequences of several interventions, regardless of patient characteristics and expectations.

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database.

BACKGROUND: Rebamipide has been widely co-prescribed with non-steroidal anti-inflammatory drugs (NSAIDs) in Japan for decades. This study aimed to evaluate the effectiveness of rebamipide in preventing upper gastrointestinal bleeding in new users of NSAIDs without risk factors of NSAID-induced ulcers other than age. METHODS: A nested case-control study was conducted using medical claims data of 1.66 million inhabitants of 17 municipalities participating in Japan's Longevity Improvement & Fair Evidence study. The cohort entry (t0) corresponded to a new user of NSAIDs for osteoarthritis or low back pain. Patients with risk factors of NSAID-induced ulcers other than age were excluded. Cases were defined as patients who underwent gastroscopy for upper gastrointestinal bleeding (occurrence date was defined as index date). A maximum of 10 controls were selected from non-cases at the index date of each case by matching sex, age, follow-up time, and type and dosage of NSAIDs. Exposure to rebamipide was defined as prescription status from t0 to index date: Non-user (rebamipide was not co-prescribed during the follow-up period), Continuous-user (rebamipide was co-prescribed from t0 with the same number of tablets as NSAIDs), and Irregular-user (neither Non-user nor Continuous-user). Conditional logistic regression analysis was conducted to estimate each category's odds ratio compared to non-users. FINDINGS: Of 67,561 individuals who met the inclusion criteria, 215 cases and 1,516 controls were selected. Compared with that of Non-users, the odds ratios and 95% confidence interval were 0.65 (0.44-0.96) for Continuous-users and 2.57 (1.73-3.81) for Irregular-users. CONCLUSIONS: Continuous co-prescription of rebamipide significantly reduced the risk of upper gastrointestinal bleeding in an Asian cohort of new users of NSAIDs with osteoarthritis or low back pain without risk factors other than age.

Pharmacological treatment of cancer pain and opioid induced nausea and vomiting: online survey and comparison with current guidelines.

PURPOSE: We assumed that in Palliative Care, even in common clinical situations, the choice of drugs differs substantially between physicians. Therefore, we assessed the practice of pharmaceutical treatment choices of physicians for cancer pain and opioid-induced nausea and vomiting (OINV) and the rationale for their choices. METHODS: An online survey was conducted with physicians covering the following domains: i) Cancer pain therapy: non-opioids in addition to opioids: choice of drug ii) prevention of OINV: choice of drug and mode of application. Current guidelines concerning cancer pain therapy and prevention of OINV were compared. RESULTS: Two-hundred-forty European physicians responded to our survey. i) Use of non-opioids in addition to opioids for the treatment of cancer pain: Only 1.3% (n = 3) of respondents never used an additional non-opioid. Others mostly used: dipyrone/metamizole (49.2%, n = 118), paracetamol/acetaminophen (34.2%, n = 82), ibuprofen / other NSAIDs (11.3%, n = 27), specific Cox2-inhibitors (2.1%, n = 5), Aspirin (0.4%, n = 1), no answer (2.9%, n = 7). ii) Antiemetics to prevent OINV: The drugs of choice were metoclopramide (58.3%, n = 140), haloperidol (26.3%, n = 63), 5-HT3 antagonists (9.6%, n = 23), antihistamines (1.3%, n = 3) and other (2.9%, n = 7); no answer (1.7%, n = 4). Most respondents prescribed the substances on-demand (59.6%, n = 143) while others (36.3%, n = 87) provided them as around the clock medication. Over both domains, most physicians answered that their choices were not based on solid evidence from randomized controlled trials (RCTs). Guidelines were inconsistent regarding if and what non-opioid to use for cancer pain and recommend anti-dopaminergic drugs for prevention or treatment of OINV. CONCLUSIONS: Physician's practice in palliative care for the treatment of cancer pain and OINV differed substantially. Respondents expressed the lack of high-quality evidence- based information from RCTs. We call for evidence from methodologically high-quality RCTs to be available to inform physicians about the benefits and harms of pharmacological treatments for common symptoms in palliative care.

Efficacy and safety of topical NSAIDs combined with physiotherapy for frozen shoulder: a randomized controlled trial.

OBJECTIVE: Frozen shoulder is a prevalent condition among individuals in their middle and later years. Invasive therapy has shown promising results in the treatment of frozen shoulders, but its widespread adoption has been hampered by high costs and the need for advanced medical technology. As a result, patients with frozen shoulders often turn to non-steroidal anti-inflammatory drugs (NSAIDs) for symptomatic relief. However, the oral administration of NSAIDs can lead to troublesome adverse effects on the gastrointestinal, cardiovascular, and urinary systems. In contrast, topical NSAIDs have gained attention for their excellent efficacy and lower adverse effects in various chronic pain conditions. Therefore, our study aimed to investigate the efficacy and safety of topical NSAIDs in improving pain and mobility among patients with frozen shoulders. PATIENTS AND METHODS: A total of 108 patients experiencing moderate to severe pain and mobility impairment due to frozen shoulder were enrolled in this study. The participants were randomly assigned to either the experimental group (n=72) or the control group (n=36). The experimental group received daily treatment with the loxoprofen hydrogel patch (LOX-P) in addition to basic rehabilitation physiotherapy. The control group was treated with flurbiprofen cataplasm (FLU-C) twice a day, along with rehabilitation physiotherapy. The primary endpoint for evaluating the efficacy of the two patches was the Constant-Murley score (CMS). Clinical symptom data, adverse events, and patient satisfaction were also recorded. RESULTS: After 14 days of treatment, the effective rate was 66.67% (n=48) in the experimental group and 41.67% (n=15) in the control group. The overall difference in the effective rates was 25.00% (95% CI=5.20-42.52; p=0.013). The safety profiles of the two topical agents were similar, with only a few adverse events reported. CONCLUSIONS: The loxoprofen hydrogel patch demonstrates a significant ability to alleviate shoulder pain and restore shoulder function in the treatment of frozen shoulder, with minimal adverse reactions. Chictr.org.cn ID: ChiCTR2100052375.

Testing of acute and sub-acute toxicity profile of novel naproxen sodium nanoformulation in male and female mice.

Nanodrugs offer promising alternatives to conventionally used over the counter drugs. Compared to its free form, therapeutic benefits, and gastric tissue safety of naproxen sodium nanoformulation (NpNF) were recently demonstrated. Essential regulatory safety data for this formulation are, however, not available. To address this, male and female BALB/c mice were subjected to acute and 14-day repeated-oral dose assessments. Our data indicate that NpNF was well tolerated up to 2000 mg/kg b.w. A 14-day subacute toxicity testing revealed that the oral administration of low dose (30 mg/kg) NpNF did not produce any adverse effects on blood profile and serum biochemical parameters. Levels of oxidative stress markers and antioxidant enzymes neared normal. Histology of selected tissues also showed no evidence of toxicity. In contrast, a ten-fold increase in NpNF dosage (300 mg/kg), demonstrated, irrespective of gender, mild to moderate toxicity (p < 0.05) in the brain, stomach, and heart tissues, while ROS, LPO, CAT, SOD, POD, and GSH levels remained unaffected in the liver, kidney, spleen, testis, and seminal vesicles. No effect on serum biochemical parameters, overall indicated a no-observed-adverse-effect level (NOAEL) is 300 mg/kg. Further increase in dosage (1000 mg/kg) significantly altered all parameters demonstrating that high dose is toxic.

Desosomes and desimicelles - a novel vesicular and micellar system for enhanced oral delivery of poorly soluble drug: Optimization of in vitro characteristics and in vivo performance.

This study introduces two innovative nanocarrier systems to improve oral drug delivery. Desosomes and desimicelles combine Deep eutectic solvent (DES) with vesicular or micellar nanosystems, respectively. These novel nanosystems integrate the DES solubilization potency for administering drugs with low aqueous solubility and the vesicular and micellar systems to bypass physiological barriers and improve poor drug bioavailability. Lornoxicam (LRX) is a BCS class II anti-inflammatory with limited aqueous solubility and rapid clearance. Desosomes and desimicelles were prepared and successfully optimized. The optimization depended on particle size, zetapotential, entrapment efficiency, and solubility. The optimized desosomes (LRX-DES-V) and desimicelles (LRX-DES-M) were pictured by transmission electron microscope. Differential scanning calorimetry (DSC) and FTIR analysis indicated the successful inclusion of LRX inside each system. Invitro LRX release profiles revealed controlled release of LRX-DES-V and LRX-DES-M, with more sustained release by the later one. In-vivo study, inflammation was induced using a carrageenan rat model, and the anti-inflammatory effect of LRX-pure, marketed product, traditional niosomes, LRX-DES-V & LRX-DES-M were determined using inhibition %, serum inflammatory cytokines, and histopathology. After 4 h of induction, LRX-DES-M (68.05%) showed a significant inhibition compared to LRX-DES-V (63.57%). LRX-DES-M also showed a better reduction in COX2, PGE2, and TNF-α (1.25-fold, 1.24-fold, and 1.36-fold inhibition), respectively, compared to LRX-DES-V. We can conclude that LRX-DES-V and LRX-DES-M showed better effects than all other groups and that LRX-DES-M might be more effective than LRX-DES-V.

Towards a greater understanding of the deep eutectic phenomenon through examination of the lidocaine-NSAID therapeutic deep eutectic systems.

Therapeutic deep eutectic solvents (THEDES) have been attracting increasing attention in the pharmaceutical literature as a promising enabling technology capable of improving physicochemical and biopharmaceutical properties for difficult-to-deliver drug compounds. The current literature has explored amide local anaesthetics and carboxylic acid nonsteroidal anti-inflammatories (NSAIDs) as commonly used THEDES formers for their active hydrogen-bonding functionality. However, little is known about what happens within the "deep eutectic" region where a range of binary compositions present simply as a liquid with no melting events detectable across experimentally achievable conditions. There is also very limited understanding of how parent compounds' physicochemical properties could impact upon the formation, interaction mechanism, and stability of the formed liquid systems, despite the significance of these information in dose adjustment, industrial handling, and scaling-up of these liquids. In the current work, we probed the "deep eutectic" phenomenon by investigating the formation and physicochemical behaviours of some chosen lidocaine-NSAID systems across a wide range of composition ratios. Our data revealed that successfully formed THEDES exhibited composition dependent Tg variations with strong positive deviations from predicted Tg values using the Gordon-Taylor theory, suggesting substantial interactions within the formed supramolecular structure. Interestingly, it was found that the parent compound's glass forming ability had a noticeable impact upon such profound interaction and hence could dictate the success of THEDES formation. It has also been confirmed that all successful systems were formed based on charge-assisted hydrogen bonding within their THEDES network, affirming the significant role of partial protonisation on achieving a profound melting point depression. More importantly, the work found that within the "deep eutectic" region there was still an ideal, or thermodynamically preferrable "THEDES point", which would exhibit excellent stability upon exposure to stress storage conditions. The discoveries of this study bring the literature one step closer to fully understanding the "therapeutic deep eutectic" phenomenon. Through correlation between parent reagents' physicochemical properties and the synthesised products' characteristics, we establish a more educated process for the prediction and engineering of THEDES.

Orally available dextran-aspirin nanomedicine modulates gut inflammation and microbiota homeostasis for primary colorectal cancer therapy.

Reversing the aggravated immunosuppression hence overgrowth of colorectal cancer (CRC) caused by the gut inflammation and microbiota dysbiosis is pivotal for effective CRC therapy and metastasis inhibition. However, the low delivery efficiency and severe dose-limiting off-target toxicities caused by unsatisfied drug delivery systems remain the major obstacles in precisely modulating gut inflammation and microbiota in CRC therapy. Herein, a multifunctional oral dextran-aspirin nanomedicine (P3C-Asp) was utilized for oral treatment of primary CRC, as it could release salicylic acid (SA) while scavenging reactive oxygen species (ROS) and held great potential in modulating gut microbiota with prebiotic (dextran). Oral P3C-Asp retained in CRC tissues for over 12 h and significantly increased SA accumulation in CRC tissues over free aspirin (10.8-fold at 24 h). The enhanced SA accumulation and ROS scavenging of P3C-Asp cooperatively induced more potent inflammation relief over free aspirin, characterized as lower level of cyclooxygenase-2 and immunosuppressive cytokines. Remarkably, P3C-Asp promoted the microbiota homeostasis and notably increased the relative abundance of strengthening systemic anti-cancer immune response associated microbiota, especially lactobacillus and Akkermansia to 6.66- and 103- fold over the control group. Additionally, a demonstrable reduction in pathogens associated microbiota (among 96% to 79%) including Bacteroides could be detected. In line with our findings, inflammation relief along with enhanced abundance of lactobacillus was positively correlated with CRC inhibition. In primary CRC model, P3C-Asp achieved 2.1-fold tumor suppression rate over free aspirin, with an overall tumor suppression rate of 85%. Moreover, P3C-Asp cooperated with αPD-L1 further reduced the tumor weight of each mouse and extended the median survival of mice by 29 days over αPD-L1 alone. This study unravels the synergistic effect of gut inflammation and microbiota modulation in primary CRC treatment, and unlocks an unconventional route for immune regulation in TME with oral nanomedicine.

Novel nano-in-micro fabrication technique of diclofenac nanoparticles loaded microneedle patches for localised and systemic drug delivery.

Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly prescribed for managing osteoarthritis, rheumatoid arthritis, and post-surgical pain. However, oral administration of diclofenac often leads to adverse effects. This study introduces an innovative nano-in-micro approach to create diclofenac nanoparticle-loaded microneedle patches aimed at localised, sustained pain relief, circumventing the drawbacks of oral delivery. The nanoparticles were produced via wet-milling, achieving an average size of 200 nm, and then incorporated into microneedle patches. These patches showed improved skin penetration in ex vivo tests using Franz-cell setups compared to traditional diclofenac formulations. In vivo tests on rats revealed that the nanoparticle-loaded microneedle patches allowed for quick drug uptake and prolonged release, maintaining drug levels in tissues for up to 72 h. With a systemic bioavailability of 57 %, these patches prove to be an effective means of transdermal drug delivery. This study highlights the potential of this novel microneedle delivery system in enhancing the treatment of chronic pain with reduced systemic side effects.

Efficacy and safety of simple analgesics for acute treatment of episodic tension-type headache in adults: a network meta-analysis.

OBJECTIVE: Tension-type headache is the most common type of primary headache and results in a huge socioeconomic burden. This network meta-analysis (NMA) aimed to compare the efficacy and safety of simple analgesics for the treatment of episodic tension-type headache (ETTH) in adults. METHODS: We searched the Cochrane Library, PubMed, Web of Science, Embase, Chinese BioMedical Literature database and International Clinical Trials Registry Platform databases for eligible randomized clinical trials reporting the efficacy and/or safety of simple analgesics. A Bayesian NMA was performed to compare relative efficacy and safety. The surface under the cumulative ranking curve (SUCRA) was calculated to rank interventions. PROSPERO registration number: CRD42018090554. RESULTS: We highlighted six studies including 3507 patients. For the 2 h pain-free rate, the SUCRA ranking was ibuprofen > diclofenac-K > ketoprofen > acetaminophen > naproxen > placebo. All drugs except naproxen reported a higher 2 h pain-free rate than placebo, with a risk ratio (RR) of 2.86 (95% credible interval, CrI: 1.62-5.42) for ibuprofen and 2.61 (1.53-4.88) for diclofenac-K. For adverse events rate, the SUCRA ranking was: metamizol > diclofenac-K > ibuprofen > lumiracoxib > placebo > aspirin > acetaminophen > naproxen > ketoprofen. The adverse event rates of all analgesics were no higher than those of placebo, except for ketoprofen. Moreover, all drugs were superior to placebo in the global assessment of efficacy. In particular, the RR of lumiracoxib was 2.47 (1.57-4.57). Global heterogeneity I2 between the studies was low. CONCLUSIONS: Simple analgesics are considered more effective and safe as a placebo for ETTH in adults. Our results suggest that ibuprofen and diclofenac-K may be the two best treatment options for patients with ETTH from a comprehensive point of view (both high-quality evidence).

To our knowledge, this is the first network meta-analysis comparing the available data on adult patients with episodic tension-type headache (ETTH) treated with different simple analgesics recommended by the current guidelines.Ibuprofen (400 mg) and diclofenac-K (12.5 mg, 25 mg) are potentially the most effective and safe treatment options, supported by high-quality evidence.