Dose Combination Research Articles

Effect of tacrolimus with mycophenolate mofetil or cyclophosphamide on the renal response in systemic lupus erythematosus patients

ObjectiveThis study aimed to determine the therapeutic efficacy of tacrolimus (TAC) with mycophenolate mofetil (MMF) or cyclophosphamide (CYC) on the renal response in systemic lupus erythematosus (SLE) patients.MethodsA retrospective cohort study based on medical data was conducted among SLE patients who took at least one of the following medicines in 2010–2021: TAC, MMF and CYC. The odds ratio (OR) and 95% confidence interval (CI) were calculated, and the synergistic interaction was estimated using logistic regression models.ResultsAmong 793 SLE patients, 27.9% patients (221 cases) achieved CR after at least 3 months. The TAC use was positively associated with CR with an adjusted OR (95% CI) of 2.82 (1.89, 4.22) overall and in subgroups of SLE patients with SLEDAI scores > 12, moderate or severe urinary protein and comorbidities. The dose-response effect on CR was also observed at TAC doses greater than 4 mg/d and more than 180 days, with adjusted ORs (95% CIs) of 5.65 (2.35, 13.55) and 3.60 (2.02, 6.41), respectively. Moreover, the combined effect of TAC with MMF or CYC was better than that of monotherapy, there was significant synergistic interactions with adjusted ORs (95% CIs) of 2.43 (1.20, 4.92) and 3.14 (1.49, 6.64), respectively, and similar results were observed for the combination of different doses of TAC with MMF or CYC.ConclusionTAC can effectively alleviate the condition of patients with SLE and may interact with MMF or CYC, which suggests that the combination therapy of TAC with MMF or CYC may produce greater benefits for patients with SLE.Trial registrationThis is a purely observational study that does not require registration.

Pulse crops as effective living mulches: An eco-conscious weed management approach

The evolution of weed management strategies from basic cultural techniques to novel, integrated approaches reflects technological advancements that promise further improvements in weed management strategies, fostering more efficient and eco-friendly farming practices. Using legume crops as living mulches for weed suppression has gained considerable attention in agricultural systems. This method involves strategically planting leguminous cover crops as intercrops to inhibit weed growth and improve soil health, potentially boosting crop yields through reduced weed pressure and enhanced nutrient availability. The successful implementation of living mulches requires careful selection of crop species, optimal planting density, and appropriate management practices. Choosing compatible legumes, optimizing planting geometry and employing suitable termination methods are essential for maximizing the weed-suppressing and soil-enhancing benefits of living mulches. The efficacy of intercropping systems in controlling weeds largely depends on intercrop components' growth rate and duration. Weed management strategies rely on understanding plant interactions, including the competitive ability of main crops at various growth stages to inhibit weed expansion. While intercropping shows promise for enhancing crop dominance over weeds, weed control efficiency varies among different intercrops due to factors affecting the intercrop-weed relationship. Smallholder farmers find this practice appealing for improving labour productivity and land use through intensification and resource utilization for maximum yield. Research on developing genotypes suitable for weed suppression and studies on combined herbicide applications and optimal dosage determination for effective control of mixed weed flora is necessary. The shift towards integrating pulse crops as a cornerstone in weed management strategies presents a promising avenue for research and application. The comparative analysis underscored in this review showcases the capacity of legumes to offer a viable alternative to synthetic herbicides and mechanical controls, paving the way for their increased adoption in diverse farming systems.

Vitamin A and D3 combinations reduce breast cancer tumor load in a postmenopausal MCF-7 xenograft mouse model in a dose- and time- dependent manner

Introduction: Earlier, we documented that a combination of vitamins A and D3 synergistically inhibited the growth of MCF-7, T48:A18 and SKBR3 breast cancer cells with the best activity seen in the ER+ cell line MCF-7. Transcriptomic analysis of treated MCF-7 cells also showed that the combination significantly upregulated the apoptosis and unfolded protein response canonical pathways, and reduced estrogen signaling. Objective: This study aimed to explore the impact of increasing vitamin A and D3 dose combinations over time in a postmenopausal model of breast cancer using ovariectomized athymic female mice bearing MCF-7 xenografts and further analyze mechanisms of action in MCF-7 cells using RNA-seq analysis. Methods: MCF-7 breast cancer cells were grown in culture for the xenograft experiments. Athymic female mice were injected with MCF-7 cells (1 x 10^6 in 100 µl of 50% Matrigel mixed with sterile PBS) via subcutaneous injection. Once the tumors reached an average volume of 100 mm³, the mice were randomly divided into four groups and treated with different vitamin A and D3 combinations. Tumor sizes and mouse body weights were monitored on a biweekly basis. After the treatment period, the mice were euthanized, and the tumors were surgically removed and measured. RNA-seq data from the treated MCF-7 cells were then further evaluated using IPA. Results: As compared with controls, treatment with vitamin A (25,000 IU) and vitamin D (10,000 IU) led to a significant reduction in tumor volume >70%, (p < 0.05-0.01) in OVX athymic mice with MCF-7 xenografts as determined by a two-tailed Student T test. Over the treatment period, the tumor volume in mice treated with vitamin A (10,000 IU) and vitamin D (5,000 IU) or vitamin A (25,000 IU) and vitamin D (5,000 IU) also trended downward and was statistically significant using one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison test (p<0.05 and p<0.0001, respectively) but was not significant using a two-tailed Student T test. In cultured MCF-7 cells, Ingenuity Pathway Analysis of mRNA-seq data showed that the vitamin A and D combination significantly altered the expression of 101 genes out of 864 in the molecular mechanisms in cancer canonical pathway, downregulating gene expression in the integrin/P13K/Akt/mTOR pathway. Conclusions: The findings showed that the combination of vitamins A and D3 effectively reduced tumor burden in a postmenopausal MCF-7 xenograft mouse model, with effects that were both dose-dependent and time-dependent. The combination also significantly altered the expression of genes in the molecular mechanisms of cancer canonical pathway in cultured MCF-7 cells. These preclinical data support the use of vitamins A and D3 in the management of estrogen-dependent breast cancers, with the caveat that higher doses and longer treatment periods may be needed to observe anti-tumor effects. Keywords: Apoptosis, autophagy, breast cancer, cell cycle, integrin, postmenopausal, P13K, tumor load, xenograft

A prospective, multicentre study evaluating safety and efficacy of a fixed dose combination of Remogliflozin etabonate, Vildagliptin, and Metformin in Indian patients with type 2 diabetes mellitus (Triad-RMV)

AimsThe ICMR INDIAB-17 study revealed a diabetes prevalence of 11.4% in India, emphasizing the need for effective treatment for glycemic control. A Phase IV study was conducted to evaluate the safety and efficacy of a Fixed Dose Combination (FDC) of Remogliflozin, Metformin and Vildagliptin (RMV) in Type 2 Diabetes Mellitus (T2DM) patients uncontrolled on Metformin plus SGLT2 inhibitor or Metformin plus DPP4 inhibitor dual therapy.MethodsA total of 215 patients (mean age: 46.4 years; 64% male, 36% female) were enrolled across multiple centers in India. The study population included patients with a baseline HbA1c ≥ 8% at the time of screening. The primary objective was to assess safety based on treatment-emergent adverse events (TEAEs), while the secondary. aim was to evaluate effectiveness in terms of glycemic (HbA1c, fasting plasma glucose, postprandial glucose) and extra-glycemic measures (renal and lipid parameters). Statistical analysis was conducted using paired t-tests and the Wilcoxon signed-rank test for within-group comparisons, and the Bonferroni correction was applied to adjust for multiple comparisons. Effectiveness was evaluated at baseline, week 12, and week 24.ResultsThe study demonstrated statistically significant reductions in mean HbA1c levels from baseline to both week 12 and week 24 (p < 0.00001). At 24, weeks, 45.1% of patients achieved target HbA1c levels of ≤ 7%. Significant reduction was also observed in fasting plasma glucose (FPG) and postprandial glucose (PPG) levels. Renal parameters remained stable or improved, and lipid profile parameters, including LDL-C and triglycerides, showed favorable changes. Adverse events of special interest, including hypoglycemia and urinary tract infections, were reported in 4.7% of patients, with no serious adverse event recorded.ConclusionsThe twice daily triple FDC of RMV was well tolerated, safe and effective in patients with Type 2 Diabetes Mellitus uncontrolled on dual drug therapy of Metformin plus SGLT2i or Metformin plus DPP4i. The treatment led to significant improvements in glycemic control and other metabolic parameters over 24 weeks, without compromising renal function or causing serious adverse events.Trial registrationCTRI, CTRI/2022/05/042581. Registered 17 May 2022, https//ctri.nic.in/Clinicaltrials/rmaindet.php? trialid=68,757&EncHid=36127.16500&modid=1&compid=19.

Hydrocortisone and vitamin B12 protect SHSY-5Y cells against glutamate excitotoxicity by altering VIP and GAL levels

Background: Prolonged elevation of extracellular glutamate levels triggers intracellular events, increases glutamate excitotoxicity, and activates apoptotic pathways, causing Alzheimer's disease (AD). The literature has reported that vitamin B12 exhibits anti-inflammatory and anti-apoptotic activities in various diseases. Hydrocortisone (HC) therapy also substantially inhibits microglia and astrocyte hyperactivation, minimizing pro-inflammatory cytokines and reducing neuroinflammation. That is why our study aimed to evaluate the therapeutic effects of HC and B12 combination on oxidative stress and VIP and GAL levels in an in vitro Alzheimer's model. Method: To create the Alzheimer's model, the neuroblastoma cell line (SH-SY5Y) was cultured. Then, all cells except the control group were treated with different doses of HC and B12 combination for 24 hours by applying Glutamate (10-5 mM) to create excitotoxicity. The results were evaluated using MTT and ELISA tests. Results: When the results were examined, it was determined that exceptionally high-dose combination groups showed protective activity against glutamate excitotoxicity. HC+B12 25 µg/ml groups observed the most statistically significant results. According to our results, oxidative stress decreased in the HC+B12 25 µg/ml group, and cell viability increased. Significant changes were also observed in Vasoactive Peptide (VIP) and Galanin (GAL) levels in correlation with other analyses obtained. Conclusion: This study is the first to report the potential of vitamin B12 combined with hydrocortisone to prevent oxidative stress and glutamate excitotoxicity in primary neurons. It provides a basis for further investigating its clinical application in neurodegenerative diseases.

Mannitol versus mannitol with hypertonic saline for brain relaxation during craniotomies using ultra-sonographic optic nerve sheath diameter

ABSTRACT Background This study compared the effect of conventional doses of mannitol alone versus combined lower doses of mannitol-hypertonic saline on brain debulking during elective craniotomies. Patients and methods Sixty participants aged 18–60 years, ASA class I or II, who were scheduled for elective supratentorial brain tumor surgery, were randomly separated into 2 equal groups. Group (M) received 5 ml/kg of 20% mannitol at the onset of the surgical incision over 15 min. Group (MH) received 2.5 ml/kg of 20% mannitol plus 2.5 ml/kg 3% hypertonic saline (HTS) at the onset of the surgical incision over 15 min. Optic nerve sheath diameter (ONSD), brain relaxation score, serum lactate, electrolytes, and surgeon’s satisfaction were measured. Results Both groups yielded similar results concerning demographic and tumor characteristics. The Optic nerve sheath diameter (ONSD) was considerably lower in group MH compared to group M just before and immediately after dural incision (p = <0.001, and 0.001) respectively. The brain relaxation was considerably more adequate in group MH when compared to group M (p = 0.001). Group MH showed significant elevation in serum sodium, chloride, and osmolarity at 60 min and at the end of surgery with negligible changes at 12- and 24-hrs postoperatively. Moreover, group M showed a significant increase in serum potassium and lactate at 60 min and at the end of surgery, with insignificant change at 12- and 24-hrs postoperatively. Surgeons were more noteworthy satisfied in group MH. Conclusion Optic nerve sheath was comparable to brain relaxation score (BRS) for assessing the brain relaxation. In comparison to mannitol alone, lower prescribed doses of mannitol in combination with hypertonic saline (HTS) have provided better intraoperative brain debulking, clinically accepted electrolyte changes, and more surgeons’ satisfaction during supratentorial brain tumor surgery.

Co-administration of coenzyme Q10 and curcumin mitigates cognitive deficits and exerts neuroprotective effects in aluminum chloride-induced Alzheimer's disease in aged mice.

Aluminum chloride (AlCl3), a known neurotoxic and Alzheimerogenic metal disrupts redox homeostasis which plays a pivotal role in pathophysiology of neurodegenerative disorders, particularly cognitive decline. The current study was designed to unveil the long-term neuroprotective outcomes and efficacy of CoQ10 and curcumin low dose (100 mg/kg each) combination in 18-months old geriatric male Balb/c mice subjected to AlCl3-prompted memory derangements (200 mg/kg in water bottles) for 28 days. The neuroprotective properties driven by antioxidant mechanisms were assessed via observing cellular pathology in key-memory related brain regions including the cornuammonis (CA3 and DG) and cortex 2/3 layer. Our outcomes revealed that AlCl3 exposure significantly reduced spatial learning and memory. In contrast, CoQ10 and curcumin combinatorial regime markedly mitigated cognitive deficits Vs. individual high-dose in AlCl3-treated animals as demonstrated by their improved performance in neurobehavioral tests such as the Y-maze, novel object recognition, passive avoidance and Morris-water maze test. Additionally, CoQ10 and curcumin co-administration restored redox balance by significantly reducing the levels of oxidative stressor (MDA) and increasing the anti-oxidant capacity (SOD,GPx). AchE is an enzyme involved in acetylcholine breakdown which negatively impacts acetylcholine levels and memory function. AlCl3 exposure elevated AchE levels in mice brains vs. treatment. This neurochemical alteration was notably reversed in the dual-treatment group. Furthermore, CoQ10 and curcumin ameliorated AlCl3-induced neurotoxicity by preserving neuronal cytoarchitecture in both cortical and hippocampal regions. In conclusion, CoQ10 and curcumin combination might attenuate memory loss induced by AlCl3-intoxication via restoring aberrant AchE activity, enhanced anti-oxidant defenses and salvaging the deleterious neuronal damage.

Abstract IA006: Progress, pitfalls and promise: the journey to effective and well tolerated DNA damage response inhibitor combinations in the clinic

A mounting body of evidence now indicates that poly(ADP-ribose) polymerase (PARP) inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. There are multiple promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness". Despite promising efficacy data, several of the combinations have been hampered by supra-additive toxicities, restricting the combination of full monotherapy doses and schedules of component drugs. I will discuss the progress, pitfalls and promise of different classes of DNA damage response (DDR) inhibitor combinations in the clinic, and discuss potential clinical strategies to develop effective and well tolerated combinations to target PARP inhibitor resistance and to widen the application of DDR agents beyond approved indications Citation Format: Timothy A. Progress, pitfalls and promise: the journey to effective and well tolerated DNA damage response inhibitor combinations in the clinic. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA006

CHD1L Inhibitor OTI-611 Synergizes with Chemotherapy to Enhance Antitumor Efficacy and Prolong Survival in Colorectal Cancer Mouse Models

Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer. It is universally treated with a combination of the DNA damaging chemotherapy drugs irinotecan, 5-Fluorouracil (5-FU), and oxaliplatin. CHD1L is a novel oncogene that plays critical roles in chromatin remodeling and DNA damage repair, as well as the regulation of malignant gene expression. We show that an inhibitor of CHD1L, OTI-611, when combined with chemotherapy significantly increases DNA damage in CRC cell lines. OTI-611 also synergizes with SN-38, 5-FU, and oxaliplatin in killing CRC tumor organoids. We also demonstrate that, as in breast cancer, OTI-611 traps CHD1L, PARP1, and PARP2 onto chromatin. The entrapment of CHD1L causes the deprotection of PAR chains in the nucleus, ultimately resulting in cell death by CHD1Li-mediated PARthanatos, as measured by AIF translocation to the nucleus. Finally, the combination of low doses of OTI-611 with irinotecan significantly reduces tumor volume and extends survival in CRC xenograft mouse models compared to irinotecan alone. The combination of standard of care chemotherapy drugs with CHD1Li represents a promising advancement in future therapeutic strategies for CRC and other cancers driven by CHD1L.

A Robust RP-HPLC Method for Simultaneous Quantification, Validation and Stability Studies on Vildagliptin (VILD), Dapagliflozin (DAPA) and Metformin Hydrochloride (METF) in its Combined Dosage Formulation

Background: Vildagliptin, Dapagliflozin and Metformin Hydrochloride are anti- hyperglycemic agents. Anti-hyperglycemic agents are drugs that stimulate insulin secretion and lower the glucose level in the blood. They were investigated as a medication for Diabetes Mellitus (DM). Various studies have reported the HPLC, HPTLC, LC/MS methods for the estimation of individuals of VILD, DAPA and METF. However, until date stability indicating HPLC analysis method has not been reported for the estimation of VILD, DAPA and METF in combined glucagon secretion in a glucose-dependent manner. Introduction: The objective of present work was to develop and validate the stability of RPHPLC method for the estimation of Vildagliptin (VILD), Dapagliflozin (DAPA) and Metformin Hydrochloride (METF) in combined dosage form. Method: In this research work, High Performance Liquid Chromatography (HPLC) was used for validation in the chromatography. In the HPLC, Methanol and Potassium Dihydrogen phosphate buffer (85:15 v/v) were used as mobile phases. HPLC analysis was performed at 230 nm. The method was validated with different parameters such as linearity, precision, accuracy, specificity, and robustness, limit of detection (LOD) and limit of quantitation (LOQ). The RF values of VILD, DAPA and METF were 6.24 ± 0.05 min, 8.34 ± 0.05 min. and 3.68 ± 0.05 min, respectively. The accuracies of drug recovery were 0.6398 %,0.3680 %, 0.6398 % and over the range of 1–4 μg/ml, 20-80 μg/ml and 15-85 μg/ml of VILD, DAPA and METF, respectively. Results: Degradation products found in stress conditions did not interfere with the detection of VILD, DAPA and METF; therefore, the proposed technique can be considered stable. Significant degradation products of VILD, DAPA and METF were obtained in an acid at METF at 2.05 ± 0.05 min. (MDP-1) and degradation product for oxidation of METF at 2.11 ± 0.05 min. (MDP-2). When alkaline hydrolysis was conducted, photolytic and thermal conditions were applied alone or in combination with METF, no degradation product of VILD, DAPA and METF was found. Conclusion: The developed and validation method was satisfactorily applied for the analysis of pharmaceutical preparations and proved specific and accurate for quality control of the cited drugs in their combined dosage form.

Effect of single-pill versus free equivalent combinations on persistence and major adverse cardiovascular events in hypertension: a real-world analysis.

Hypertension guidelines recommend the use of single-pill combinations (SPCs) of antihypertensive drugs to improve treatment persistence and blood pressure control. This study aimed to investigate the long-term effects of ramipril/amlodipine (R/A) SPC versus free equivalent dose combinations (FEC) on cardiovascular outcomes and treatment persistence. This retrospective, observational study analysed the database of the Hungarian National Health Insurance Fund. The study included patients with hypertension aged at least 18 years who were initiated on R/A SPC or FEC of different dose combinations (R/A 5/5, 5/10, 10/5 and 10/10 mg) between 2012 and 2018, with follow-up for up to 60 months. Imbalances in baseline characteristics were reduced with propensity score-based sub-classification. All analyses were performed with Cox proportional hazard model and propensity score sub-classification to adjust the imbalances in baseline characteristics. Drug persistence and MACEs were the primary and secondary endpoints, respectively. Overall, 104 882 patients with SPC and 68 324 patients with FEC-treated hypertension were included. The R/A 5/5 mg combination represented the largest proportion (62%). The nonpersistence rate was significantly lower with SPC than with FEC from month 1 to month 24 in the R/A 5/5 mg combination (P < 0.001) and during the entire observation period in the remaining combinations. The MACE rate was significantly reduced with all R/A SPCs versus FECs. No effects on age and sex on both endpoints were noted. This study further supports the beneficial effects of the use of SPC on 60-month persistence and MACEs in hypertension.

Efficacy of Dapagliflozin + Sitagliptin + Metformin Versus Sitagliptin + Metformin in T2DM Inadequately Controlled on Metformin Monotherapy: A Multicentric Randomized Trial.

A slower adoption rate of fixed dose combinations (FDC) in diabetes management is partly due to insufficient data. This study evaluates the safety and efficacy of an FDC of dapagliflozin + sitagliptin + metformin hydrochloride extended release (XR), compared to a dual FDC of sitagliptin + metformin hydrochloride XR among patients with type2 diabetes mellitus (T2DM) with poor glycemic control when treated with metformin monotherapy. A total of 274 patients with T2DM were randomized (1:1) to either armX, receiving FDC of dapagliflozin (10mg) + sitagliptin (100mg) + metformin hydrochloride XR (1000mg) (Dapa + Sita + Met) tablets, or armY, receiving sitagliptin phosphate (100mg) + metformin hydrochloride XR (1000mg) (Sita + Met) tablets, and treated for 16weeks. The outcome measures included changes in hemoglobinA1c (HbA1c)(%), fasting plasma glucose (FPG), 2-h post-prandial glucose (PPG), weight, and the proportion of patients achieving target HbA1c levels of < 7.0% by week16 of the study period. The reduction in HbA1c at week16 was significantly higher in armX than in armY [estimated treatment difference (ETD), -0.65% (95%CI -0.76 to -0.53; P < 0.0001)]. ArmX showed a marked decrease in FPG [ETD -15.42mg/dl; 95%CI (17.63, 13.22; P < 0.0001)], PPG [ETD -30.39mg/dl; 95%CI (35.59, 25.19; P < 0.0001)], and weight [ETD -1.47kg; 95%CI (1.59, 1.28; P < 0.0001)] after 16weeks. In armX, 54% of patients reached HbA1c < 7.0% compared to 29.9% in armY. The incidence of adverse events was comparable [13.14% (armX) vs 12.4% (armY)]. There was no severe hypoglycemia-led treatment discontinuation. Among patients with T2DM who have poor glycemic control with metformin monotherapy, triple FDC (Dapa + Sita + Met) effectively helped achieve better glycemic response compared to dual FDC (Sita + Met), with a comparable safety and tolerability profile. CTRI/2022/01/039857.

First-in-human Evaluation of Safety and Dosimetry of [64Cu]FBP8: A fibrin-binding PET Probe.

This study presents for the first time in humans the biodistribution, clearance and dosimetry estimates of [64Cu]Fibrin Binding Probe #8 ([64Cu]FBP8) in healthy subjects. [64Cu]FBP8-PET previously demonstrated its potential in two recent applications: thrombus imaging and pulmonary fibrosis. This prospective study included 8 healthy subjects to evaluate biodistribution, safety and dosimetry estimates of [64Cu]FBP8, a fibrin-binding positron emission tomography (PET) probe. All subjects underwent up to 3 sessions of PET/Magnetic Resonance Imaging (PET/MRI) 0-2h, 4h and 24h post injection. Dosimetry estimates were obtained using OLINDA 2.2 software. Subjects were injected with 400 MBq of [64Cu]FBP8. Subjects did not experience adverse effects due to the injection of the probe. [64Cu]FBP8 PET images demonstrated fast blood clearance (half-life = 67min) and renal excretion of the probe, showing low background signal across the body. The organs with the higher doses were: the urinary bladder (0.075 vs. 0.091 mGy/MBq for males and females, respectively); the kidneys (0.050 vs. 0.056 mGy/MBq respectively); and the liver (0.027 vs. 0.035 mGy/MBq respectively). The combined mean effective dose for males and females was 0.016 ± 0.0029 mSv/MBq, lower than the widely used [18F]fluorodeoxyglucose ([18F]FDG, 0.020mSv/MBq). This study demonstrates the following properties of the [64Cu]FBP8 probe: low dosimetry estimates; fast blood clearance and renal excretion; low background signal; and whole-body acquisition within 20min in a single session. These properties provide the basis for [64Cu]FBP8 to be an excellent candidate for whole-body non-invasive imaging of fibrin, an important driver/feature in many cardiovascular, oncological and neurological conditions.

Synergistic‐like decreases in alcohol intake following combined pharmacotherapy with GLP‐1 and amylin in male rats

Background and PurposeThe limited effectiveness of current pharmacological treatments for alcohol use disorder (AUD) highlights the need for novel therapies. These may involve the glucagon‐like peptide‐1 receptor or the amylin receptor, as treatment with agonists targeting either of these receptors lowers alcohol intake. The complexity of the mechanisms underlying AUD indicates that combining agents could enhance treatment efficacy. While a combination of amylin receptor and GLP‐1 receptor agonists reduced food intake and body weight synergistic‐like, its influence on alcohol intake is unknown.Experimental ApproachEffects of a range of dose‐combinations of GLP‐1 receptor (dulaglutide) and amylin receptor (salmon calcitonin; sCT) agonists on alcohol intake were explored in male and female rats. We used dose combinations that either lowered alcohol intake as monotherapy (0.1 mg·kg−1 + 5 μg·kg−1), or that did not affect alcohol consumption per se (0.075 mg·kg−1 + 2 μg·kg−1).Key ResultsAcute administration of dulaglutide and sCT (0.1 mg·kg−1 + 5 μg·kg−1) reduced alcohol intake in males, but not in females. When higher doses were evaluated in female rats, a decrease in alcohol intake was observed. Furthermore, the low dose combination (0.075 mg·kg−1 + 2 μg·kg−1) decreased, in in a synergistic‐like manner, alcohol intake and prevented abstinence‐induced drinking without affecting kaolin intake in males. However, tolerance developed during sub‐chronic treatment.Conclusion and ImplicationsCollectively, these findings show that the combination of dulaglutide and sCT decreased, in in a synergistic‐like manner, alcohol consumption in male rats. Contrarily, higher doses are required for females.

Microwave-assisted oxidation of naphthenic acids in aqueous phase

Naphthenic acids (NAs) in oil sands processing wastewater (OSPW) pose a significant environmental risk. This study investigates the effectiveness of three oxidants, hydrogen peroxide (H2O2), persulfate (PS), and percarbonate (PC), in degrading synthetic OSPW containing a commercial mixture of NAs (50 mg/L) via microwave-assisted oxidation catalyzed by graphite (500 mg/L). Initial experiments using stoichiometric oxidant doses revealed that PC led to NAs’ carboxylation, increasing Total Organic Carbon (TOC). H2O2 was only effective at acidic pH (pH: 3), while PS achieved high mineralization (>85 %) in all cases, whilst decreasing the pH to 2.Although PS efficiently mineralized NAs, it generates sulfate, increasing salinity and hindering water reuse or discharge. To address this, a sequential oxidation process was proposed. Firstly PS was employed to initiate degradation and decrease pH, followed by H2O2 for further purification. A combined dose of 30% stoichiometric PS and 70% stoichiometric H2O2 was selected to treat OSPW in both ultrapure and brackish water matrices. The microwave-assisted PS-H2O2 process demonstrated significant potential, achieving 74% TOC removal in 20 min. Furthermore, toxicity assessments using Artemia salina confirmed a reduction in NAs' toxicity after treatment.

Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria

BackgroundThe combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results.MethodsTwenty-four healthy adults enrolled over three consecutive cohorts were inoculated with Plasmodium falciparum-infected erythrocytes on day 0. Participants were randomized within each cohort to one of seven dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42 ± 2. The general pharmacodynamic interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study.ResultsFor a dose of 800 mg artefenomel administered with 640 mg, 960 mg, or 1440 mg piperaquine, the simulated adequate parasitological response at day 28 (APR28), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR28 in the phase 2b trial of 67.0%, 65.5%, and 75.4%, respectively.ConclusionsThese results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development.Trial registrationThis study was registered on ClinicalTrials.gov on 11 May 2018 with registration number NCT03542149.

Evaluation of the Effect of Probiotic Supplementation on Intestinal Barrier Integrity and Epithelial Damage in Colitis Disease: A Systematic Review.

Previous reviews have focused on the effects of probiotics on colitis, but there is a need to understand their impact on barrier integrity and tight junction protein improvement in colitis. This study aimed to systematically examine the effects of probiotic use on barrier integrity in colitis disease. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search in PubMed, Web of Science, Scopus, and Cochrane databases identified 2537 articles. As a result of the search, 2537 articles were accessed. Study results were summarized descriptively through discussions by intervention conditions, study population, measurement methods, and key findings. The included studies were independently reviewed and all authors reached consensus on the quality and major findings from the included articles. Forty-six studies that met the inclusion criteria were analyzed within the scope of the systematic review. Although the study primarily utilized probiotics from the Lactobacillaceae family (notably, L casei, L reuteri, L rhamnosus, L plantarum, and L pentosus) and the Bifidobacteriaceae family (notably, B breve, B animalis, and B dentium), other probiotics also demonstrated positive effects on tight junction proteins. These effects are attributed to the production of bioactive and metabolic compounds, as well as short-chain fatty acids, which combat pathogens and reduce anti-inflammatory agents. However, it was observed that the effects of these probiotics on tight junction proteins varied depending on the strain and dose. The beneficial effects of probiotics on remission in inflammatory bowel disease are well documented. Studies show that probiotics generally improve intestinal barrier function, but factors such as dose, duration, and bacterial species combinations need further clarification. Additionally, comprehensive studies are needed to understand how improved barrier function affects absorption in individuals. PROSPERO registration no. CRD42023452774.

1. COMBINATION OF TRADITIONAL CO2 LASER AND PULSE DOSES ITRACONAZOLE IN PRIMARY TOTAL DYSTROPHIC ONYCHOMYCOSIS (TDO) TREATMENT: A CASE REPORT

Onychomycosis is one of the most common nail diseases. Treatment of onychomycosis, mainly moderate to severe, can be very challenging, expensive and time consuming. Compared with topical and oral therapies, laser treatment offers a more promising modality for the treatment of severe or resistant cases. To enhance the effect, the combination of oral itraconazole pulse doses with mechanical removal of the affected part of the nail plate by using ablative CO2 laser are investigated. Here, we report a total dystrophic onychomycosis case successfully treated with traditional CO 2 laser and pulse doses itraconazole. This suggests the potential of conventional ablative CO 2 laser in the treatment of severe onychomycosis.

A newly developed method for assessing co-exposure to free dose combinations: a proof-of-concept study using antihypertensive medications in Danish registers

BackgroundElevated blood pressure is a major risk factor for severe medical conditions. Adherence to antihypertensive medication, especially in free-dose combinations, poses a significant challenge. This study aims to develop a novel method for assessing co-exposure to free-dose antihypertensive medications using secondary data sources.MethodsA register-based cohort study was conducted on individuals aged 65 years or older in Denmark who initiated antihypertensive therapy from 1996 to 2016 and followed for 730 days from the index date. A new method was developed to assess co-exposure to antihypertensive medications through redeemed prescriptions, treatment episodes, and overlapping medication events. The method's accuracy was evaluated using a random sample of 400 individuals.ResultsA total of 1,021,819 individuals were included in the study, with a mean age of 68.8 years, and 53.7% were women. The method achieved 100% accuracy in identifying co-exposure periods. During the early stage of the follow-up (0–180 days), 54.1% of individuals were co-exposed to at least two antihypertensive medications, while 37.5% were co-exposed during the late stage of the follow-up period (181–730 days). The most frequent antihypertensive combinations included bendroflumethiazide and potassium with either amlodipine or enalapril in the early (13.2% and 12.5% of patients, respectively) and late stages (16.9% and 15.0% of patients, respectively).ConclusionsThe newly developed method effectively assesses co-exposure to antihypertensive medications, overcoming previous limitations. The findings reveal common co-exposure combinations and evolving trends in antihypertensive medication use among older individuals, reflecting changes in clinical practice and guidelines over two decades.

Impact of radiation dose and iterative reconstruction (IR) level on low-contrast detectability with 4-AFC approach

This study evaluated impacts of dose and iterative reconstruction (IR) level on low-contrast detectability in images of AAPM CT Performance phantom using a 4-alternative forced choice (4-AFC) approach. Five medical physicists detected low-contrast and small objects having size of 3.0 mm with the 4-AFC method. The tests were conducted at three different radiation doses (35.8 mGy, 54.1 mGy, and 72.1 mGy) at various IR levels from 0% to 100%. The total number of 4-AFC questions was 330 questions in which each observer answered the questions in 60 minutes. Percent correct answers increase as the IR level increases from 0 to 100%. The percent correct answers also increase as the dose increases from 34.8 mGy to 72.1 mGy. 100% correct answers start at IR levels of 70, 60, and 40% for doses of 34.8, 54.1, and 72.1 mGy, respectively. Conclusions: Increasing IR level and dose improve image quality, i.e., higher average percent correct answers. At IR levels around 50%, the average percent correct is close to the maximum (around 100%) for all radiation doses. An optimal combination of IR and radiation dose can produce good image quality with lower radiation dose.