Search Results (22)

Recent breakthroughs in cancer immunotherapy have shown remarkable success, yet treatment efficacy varies significantly among individuals. Emerging evidence highlights the gut microbiota as a key modulator of immunotherapy response, while vitamin D (VD), an immunomodulatory hormone, has garnered increasing attention for its potential interactions with gut microbiota and immunotherapy outcomes. However, the precise mechanisms and clinical applications of VD in this context remain controversial. This study systematically analyzed peer-reviewed evidence from PubMed, Scopus, Web of Science, PsycINFO, and MEDLINE (January 2000–May 2025) to investigate the complex interplay among VD, gut microbiota, and cancer immunotherapy. This review demonstrates that VD exerts dual immunomodulatory effects by directly activating immune cells through vitamin D receptor (VDR) signaling while simultaneously reshaping gut microbial composition to enhance antitumor immunity. Clinical data reveal paradoxical outcomes: optimal VD levels correlate with improved immunotherapy responses and reduced toxicity in some studies yet are associated with immunosuppression and poorer survival in others. The bidirectional VD–microbiota interaction further complicates this relationship: VD supplementation enriches beneficial bacteria, which reciprocally regulate VD metabolism and amplify immune responses, whereas excessive VD intake may disrupt this balance, leading to dysbiosis and compromised therapeutic efficacy. These findings underscore the need to elucidate VD’s dose-dependent and microbiota-mediated mechanisms to optimize its clinical application in immunotherapy regimens. Future research should prioritize mechanistic studies of VD’s immunoregulatory pathways, personalized strategies accounting for host–microbiota variability, and large-scale clinical trials to validate VD’s role as an adjuvant in precision immunotherapy. Full article

Background/Objectives: Avatrombopag (AVA), a thrombopoietin receptor agonist used to treat thrombocytopenia in patients with chronic liver disease, exhibits significant pharmacokinetic (PK) variability, particularly under fasting conditions. This study investigates the combined influence of food intake and genetic polymorphisms in CYP2C9 and ABCB1 on the PK and pharmacodynamics (PD) of AVA, with the goal of informing individualized dosing strategies. Methods: A pharmacogenetic analysis was conducted in 92 healthy participants, who received 20 mg of AVA under both fasting and fed conditions. A population PK/PD model was developed to evaluate the covariates effects on the PK variability. Monte Carlo simulations were used to predict AVA exposure and platelet count profiles under diverse dosing scenarios. Results: Food intake significantly reduced PK variability, with approximately 50% reductions in clearance (CL/F) and volume of distribution (Vd/F) compared to fasting conditions. Under fed conditions, CYP2C9 intermediate metabolizers showed a 1.70-fold increase in exposure compared to normal metabolizers, but this difference was not observed under fasting conditions. ABCB1 polymorphisms showed minimal impact, with the exception of ABCB1 (C1236T) heterozygotes, which exhibited 1.37-fold increased exposure. Despite the observed PK variability, simulations demonstrated a consistent platelet count response across dosing regimens. Conclusions: While food intake and genetic polymorphisms in CYP2C9 and ABCB1 influenced AVA PK, these factors may not require dose adjustments, as platelet count responses remained consistent across genotypes and dosing conditions in the Chinese participants. These findings support simplified dosing strategies without the need for pharmacogenetic testing in Chinese individuals and may contribute to more individualized thrombocytopenia management. Full article

Fungal diseases, despite their low incidence in sharks and rays, are considered emerging diseases in this group of animals and can lead to high mortality rates despite treatment. The information available related to the treatment of fungal diseases in elasmobranchs is limited and is frequently based on the empirical knowledge provided by the professionals and clinicians working with these species. The use of azole antifungal drugs, especially voriconazole, has shown promise as a potential treatment option for fungal infections in elasmobranchs, with favorable outcomes in some registered cases. However, scientific knowledge regarding azole pharmacokinetics (PK) in fish remains limited, and despite the recent publication of a PK study with voriconazole in rays, there are still no published PK studies for azoles in sharks. In this study, voriconazole was administered at 4 mg/kg intravenously (IV) and intramuscularly (IM) to nursehound sharks (Scyliorhinus stellaris) (n = 6). Blood samples were collected before administration and at nine predetermined time intervals afterwards (0.25, 0.5, 1, 1.5, 2, 4,8,12, 24, and 36 h). Plasma concentrations were determined using a validated high-performance liquid chromatography (HPLC) method, and pharmacokinetic (PK) parameters were estimated using a non-compartmental model. The mean peak plasma concentrations (C_max) ± SEM after IM administration was 3.00 ± 0.23 µg/mL. The volume of distribution (Vd) after IV and IM administration resulted in 1.39 ± 0.09 L/kg and 1.50 ± 0.18 L/kg, respectively, showing no statistically significant differences between the two routes. Clearance (Cl) values were 0.12 ± 0.01 mL/min after IV administration and 0.29 ± 0.05 mL/min after IM administration. No adverse effects were detected during the study or four weeks after administration. These results support the administration of IV and IM voriconazole in sharks; however, additional studies on toxicity and pharmacodynamics are necessary. Moreover, further research on the susceptibility of fungal pathogens affecting elasmobranchs is needed to establish an optimal dosing regimen for IM voriconazole in the treatment of mycosis in sharks. Full article

Objectives: The objectives of this study were to evaluate the structural and functional outcomes after the loading phase with brolucizumab in switched patients with diabetic macular edema (DME) and to identify potential predictive biomarkers of treatment response. Methods: A total of 28 eyes with DME, switched to brolucizumab, were retrospectively reviewed. Main outcomes during the follow-up period, up to 6 weeks after the fifth injection, included changes in best-corrected visual acuity (BCVA), central subfield thickness (CST), macular volume, subfoveal choroidal thickness, intraretinal and subretinal fluid (IRF and SRF), cyst dimension including maximal horizontal cyst diameter (MHCD), maximal vertical cyst diameter (MVCD), width-to-height ratio (WHR), foveal avascular zone (FAZ) dimension, and vessel density (VD). Results: At the last follow-up, BCVA was significantly improved (p = 0.003). Significant reduction of CST was demonstrated after each injection time point (p < 0.05), and a dry macula was detected in 64.3% of patients at the last follow-up. The WHR was 1.23 ± 0.46, and a negative correlation to final CST (p < 0.0001) was found. In FAZ and VD analysis, no significant variation was detected. At the last disease activity assessment, the treatment regimen was q12 in 64% of patients. Conclusions: Brolucizumab leads to anatomical and functional improvements in switched eyes affected by DME. WHR may represent a predictive biomarker of treatment response. Full article

The present study aims to characterise the pharmacokinetics of rifampicin (RIF) in tuberculosis (TB) patients with and without HIV co-infection, considering the formation of 25-O-desacetyl-rifampicin (desRIF). It is hypothesised that the metabolite formation, HIV co-infection and drug formulation may further explain the interindividual variation in the exposure to RIF. Pharmacokinetic, clinical, and demographic data from TB patients with (TB-HIV+ group; n = 18) or without HIV (TB-HIV− group; n = 15) who were receiving RIF as part of a four-drug fixed-dose combination (FDC) regimen (RIF, isoniazid, pyrazinamide, and ethambutol) were analysed, along with the published literature data on the relative bioavailability of different formulations. A population pharmacokinetic model, including the formation of desRIF, was developed and compared to a model based solely on the parent drug. HIV co-infection does not alter the plasma exposure to RIF and the desRIF formation does not contribute to the observed variability in the RIF disposition. The relative bioavailability and RIF plasma exposure were significantly lower than previously reported for the standard regimen with FDC tablets. Furthermore, participants weighting less than 50 kg do not reach the same RIF plasma exposure as compared to those weighting >50 kg. In conclusion, as no covariate was identified other than body weight on CL/F and Vd/F, low systemic exposure to RIF is likely to be caused by the low bioavailability of the formulation. Full article

The activation of the vitamin D receptor (VDR) in the ileum has been shown to regulate Paneth cell-specific defensins, a large family of antimicrobial peptides; hence, this may serve as a potential mechanism to maintain intestinal homeostasis. Previously, we have demonstrated that a combination of vitamin D₃ (VD) and fructooligosaccharides (FOSs) upregulates colonic Vdr in mice. Here, we aim to examine the effect of VD, alone or in combination with FOSs, on intestinal barrier integrity and the secretion of antimicrobial peptides, as well as the gut microbial community. Male and female C57BL/6J mice at 6 weeks old were randomized into three groups to receive the following dietary regimens (n = 10/sex/group) for 8 weeks: (1) standard AIN-93G control diet (CTR), (2) CTR + 5000 IU vitamin D₃ (VD), and (3) VD + 5% fructooligosaccharides (VF). VD and VF differentially regulated the mRNA expressions of tight junction proteins in the colon and ileum. VF suppressed the upregulation of colonic ZO-1 and occludin, which was induced by VD supplementation alone. In the ileum, occludin but not ZO-1 was upregulated 20-fold in the VF-treated mice. While VD did not alter the mRNA expressions of Vdr and defensins in the ileum, these targets were downregulated by VF. Microbial analysis further reveals a shift of microbial beta diversity and a reduction in Romboutsia ilealis, a pathobiont, in VF-treated mice. Though the implications of these phenotypical and microbial changes remain to be determined, the administration of FOSs in the presence of VD may serve as an effective dietary intervention for maintaining intestinal homeostasis. Full article

This study aimed to characterize the impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics (PK) of meropenem in neonates and children and to provide recommendations for meropenem dosing in this specific population of patients. Therapeutic drug monitoring (152 meropenem plasma concentrations) data from 45 patients (38 received ECMO) with a body weight (BW) of 7.88 (3.62–11.97) kg (median (interquartile range)) and postnatal age of 3 (0–465) days were collected. The population PK analysis was performed using NONMEM V7.3.0. Monte Carlo simulations were performed to assess the probability of target achievement (PTA) for 40% of time the free drug remained above the minimum inhibitory concentration (fT > MIC) and 100% fT > MIC. BW was found to be a significant covariate for the volume of distribution (Vd) and clearance (CL). Additionally, continuous renal replacement therapy (CRRT) was associated with a two-fold increase in Vd. In the final model, the CL and Vd for a typical patient with a median BW of 7.88 kg that was off CRRT were 1.09 L/h (RSE = 8%) and 3.98 L (14%), respectively. ECMO did not affect meropenem PK, while superimposed CRRT significantly increased Vd. We concluded that current dosing regimens provide acceptably high PTA for MIC ≤ 4 mg/L for 40% fT > MIC, but individual dose adjustments are needed for 100% fT > MIC. Full article

Background: The purpose of the present study was to evaluate the effectiveness of a misoprostol vaginal insert as an induction-of-labor (IOL) agent in women with an unfavorable cervix (Bishop score < 2) in achieving vaginal delivery (VD) within 48 h, depending on the gestational week, with particular emphasis on the cesarean section (CS) percentage, intrapartum analgesia application and possible side effects, such as tachysystole ratio. Methods: In this retrospective observational study involving 6000 screened pregnant patients, 190 women (3%) fulfilled the study inclusion criteria and underwent vaginal misoprostol IOL. The pregnant women were collected into three groups: patients who delivered at up to 37 weeks of gestation (<37 Group)—42 patients; patients who delivered between 37 and 41 weeks of gestation (37–41 Group)—76 patients; and patients who delivered after 41 weeks of gestation (41+ Group)—72 patients. The outcomes included time to delivery and mode of delivery, rate of tachysystole, need for intrapartum analgesia, and need for oxytocin augmentation. Results: Most of the patients delivered vaginally (54.8% in <37 Group vs. 57.9% in 37–41 Group vs. 61.1% in 41+ Group). A total of 89.5% (170/190) of patients delivered within 48 h (<37 Group—78.6% vs. 37–41 Group—89.5% vs. 41+ Group—95.8%). Statistical significance was demonstrated for the increased rate of vaginal deliveries and shortened time to delivery in the 41+ weeks group (p = 0.0026 and p = 0.0038). The indications for cesarean section were as follows: abnormal CTG pattern vs. lack of labor progression: 42.1% vs. 57.9% in <37 Group, 59.4% vs. 40.6% in 37–41 Group and 71.4% vs. 28.6% in 41+ Group. Statistical significance was demonstrated for the increased rate of abnormal CTG patterns as cesarean section indications in the 41+ Group (p = 0.0019). The need for oxytocin augmentation in each group was: 35.7% in <37 Group vs. 19.7% in 37–41 Group vs. 11.1% in 41+ Group. Statistical significance was shown for decreased need for oxytocin augmentation in +41 Group (p = 0.0016). The need for intrapartum anesthesia, depending on the group, was: 78.6% in <37 Group vs. 82.9% in 37–41 Group vs. 83.3% in 41+ Group. Statistical significance was demonstrated for increased need for intrapartum anesthesia application during labor in +41 Group (p = 0.0018). The prevalence of hyperstimulation was similar in all three groups (4.8% vs. 7.9% vs. 5.6% p > 0.05). Conclusions: The misoprostol vaginal regimen for IOL used in our study is effective in achieving vaginal delivery within 48 h. In post-term women, the use of this regimen is characterized by an increased rate of vaginal deliveries, a shorter time to delivery and a lower need for oxytocin. Full article

While the relevance of inter-ethnic differences to the pharmacokinetic variabilities of antimicrobials has been reported in studies recruiting healthy subjects, differences in antimicrobial pharmacokinetics between Asian and non-Asian patients with severe pathologic conditions require further investigation. For the purpose of describing the potential differences in antimicrobial pharmacokinetics between Asian and non-Asian populations, a systematic review was performed using six journal databases and six theses/dissertation databases (PROSPERO record CRD42018090054). The pharmacokinetic data of healthy volunteers and non-critically ill and critically ill patients were reviewed. Thirty studies on meropenem, imipenem, doripenem, linezolid, and vancomycin were included in the final descriptive summaries. In studies recruiting hospitalised patients, inconsistent differences in the volume of distribution (V_d) and drug clearance (CL) of the studied antimicrobials between Asian and non-Asian patients were observed. Additionally, factors other than ethnicity, such as demographic (e.g., age) or clinical (e.g., sepsis) factors, were suggested to better characterise these pharmacokinetic differences. Inconsistent differences in pharmacokinetic parameters between Asian and non-Asian subjects/patients may suggest that ethnicity is not an important predictor to characterise interindividual pharmacokinetic differences between meropenem, imipenem, doripenem, linezolid, and vancomycin. Therefore, the dosing regimens of these antimicrobials should be adjusted according to patients’ demographic or clinical characteristics that can better describe pharmacokinetic differences. Full article

Data on octogenarian patients with MM are scarce, and optimal management remains controversial. We report a retrospective cohort of unselected octogenarian patients with NDMM treated with bortezomib dexamethasone (Vd). Seventy-four patients were treated with an initial doublet therapy (Vd regimen, 2–3 cycles, induction). A dose escalation with an adjunction of melphalan or cyclophosphamide was proposed for patients who had an insufficient response after induction and who could tolerate it. In responders, the treatment was continued until progression or a plateau response for 6 months (consolidation). The overall response rate was 73%. After a median follow-up of 31.4 months, median progression-free survival (PFS) and overall survival (OS) were 13.2 and 26.9 months, respectively. PFS and OS of patients with ECOG PS < 3 (25.4 and 54.9 months, respectively) were better in comparison to PFS and OS of patients with ECOG PS ≥ 3 (9.3 and 11.3 months, respectively). Thirteen patients (17.6%) died during induction. Twelve patients (16.2%) died during consolidation. In conclusion, a conservative therapeutic strategy based on Vd resulted in a good response rate. However, the survival remains poor in the population of patients with an ECOG PS ≥ 3, mainly because of early mortality not related to progressive disease. Full article

For patients with myelofibrosis, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment to date. Busulfan-based conditioning regimens are commonly used, although high inter-individual variability (IIV) in busulfan drug exposure makes individual dose selection challenging. Since data regarding the IIV in patients with myelofibrosis are sparse, this study aimed to develop a population pharmacokinetic (PopPK) model of busulfan and its metabolite sulfolane in patients with myelofibrosis. The influence of patient-specific covariates on the pharmacokinetics of drug and metabolite was assessed using non-linear mixed effects modeling in NONMEM^®. We obtained 523 plasma concentrations of busulfan and its metabolite sulfolane from 37 patients with myelofibrosis. The final model showed a population clearance (CL) and volume of distribution (V_d) of 0.217 L/h/kg and 0.82 L/kg for busulfan and 0.021 L/h/kg and 0.65 L/kg for its metabolite. Total body weight (TBW) and a single-nucleotide polymorphism of glutathione-S-transferase A1 (GSTA1 SNP) displayed a significant impact on volume of distribution and metabolite clearance, respectively. This is the first PopPK-model developed to describe busulfan’s pharmacokinetics in patients with myelofibrosis. Incorporating its metabolite sulfolane into the model not only allowed the characterization of the covariate relationship between GSTA1 and the clearance of the metabolite but also improved the understanding of busulfan’s metabolic pathway. Full article

Chemoresistance to 5-fluorouracil (5-FU) is common during colorectal cancer (CRC) treatment. This study measured the chemotherapeutic effects of 5-FU, active vitamin D₃ (VD₃), and/or metformin single/dual/triple regimens as complementary/alternative therapies. Ninety male mice were divided into: negative and positive (PC) controls, and 5-FU, VD₃, Met, 5-FU/VD₃, 5-FU/Met, VD₃/Met, and 5-FU/VD₃/Met groups. Treatments lasted four weeks following CRC induction by azoxymethane. Similar regimens were also applied in the SW480 and SW620 CRC cell lines. The PC mice had abundant tumours, markedly elevated proliferation markers (survivin/CCND1) and PI3K/Akt/mTOR, and reduced p21/PTEN/cytochrome C/caspase-3 and apoptosis. All therapies reduced tumour numbers, with 5-FU/VD₃/Met being the most efficacious regimen. All protocols decreased cell proliferation markers, inhibited PI3K/Akt/mTOR molecules, and increased proapoptotic molecules with an apoptosis index, and 5-FU/VD₃/Met revealed the strongest effects. In vitro, all therapies equally induced G1 phase arrest in SW480 cells, whereas metformin-alone showed maximal SW620 cell numbers in the G0/G1 phase. 5-FU/Met co-therapy also showed the highest apoptotic SW480 cell numbers (13%), whilst 5-FU/VD₃/Met disclosed the lowest viable SW620 cell percentages (81%). Moreover, 5-FU/VD₃/Met revealed maximal inhibitions of cell cycle inducers (CCND1/CCND3), cell survival (BCL2), and the PI3K/Akt/mTOR molecules alongside the highest expression of cell cycle inhibitors (p21/p27), proapoptotic markers (BAX/cytochrome C/caspase-3), and PTEN in both cell lines. In conclusion, metformin monotherapy was superior to VD₃, whereas the 5-FU/Met protocol showed better anticancer effects relative to the other dual therapies. However, the 5-FU/VD₃/Met approach displayed the best in vivo and in vitro tumoricidal effects related to cell cycle arrest and apoptosis, justifiably by enhanced modulations of the PI3K/PTEN/Akt/mTOR pathway. Full article

Preclinical, clinical, and epidemiological studies indicate that vitamin D3 (VD) deficiency is a risk factor for the development of breast cancer. Underlying mechanisms include the ability of calcitriol to induce cell differentiation, inhibit oncogenes expression, and modify different signaling pathways involved in the control of cell proliferation. In addition, calcitriol combined with different kinds of antineoplastic drugs has been demonstrated to enhance their beneficial effects in an additive or synergistic fashion. However, a recognized adjuvant regimen based on calcitriol for treating patients with breast cancer has not yet been fully established. Accordingly, in the present work, we review and discuss the preclinical and clinical studies about the combination of calcitriol with different oncological drugs, aiming to emphasize its main therapeutic benefits and opportunities for the treatment of this pathology. Full article

Asthma oxidative stress disturbances seem to enable supplementary proinflammatory pathways, thus contributing to disease development and severity. The current study analyzed the impact of two types of oral vitamin D (VD) supplementation regimens on the redox balance using a murine model of acute ovalbumin-induced (OVA-induced) asthmatic inflammation. The experimental prevention group received a long-term daily dose of 50 µg/kg (total dose of 1300 µg/kg), whereas the rescue group underwent a short-term daily dose of 100 µg/kg (total dose of 400 µg/kg). The following oxidative stress parameters were analyzed in serum, bronchoalveolar lavage fluid (BALF) and lung tissue homogenate (LTH): total oxidative status, total antioxidant response, oxidative stress index, malondialdehyde and total thiols. Results showed that VD significantly reduced oxidative forces and increased the antioxidant capacity in the serum and LTH of treated mice. There was no statistically significant difference between the two types of VD supplementation. VD also exhibited an anti-inflammatory effect in all treated mice, reducing nitric oxide formation in serum and the expression of nuclear factor kappa B p65 in the lung. In conclusion, VD supplementation seems to exhibit a protective role in oxidative stress processes related to OVA-induced acute airway inflammation. Full article

Background: Ceftolozane-tazobactam is a new antibiotic against multidrug-resistant pathogens such as Pseudomonas aeruginosas. Ceftolozane-tazobactam dosage is still uncertain in children, especially in those with renal impairment or undergoing continuous renal replacement therapy (CRRT). Methods: Evaluation of different ceftolozane-tazobactam dosing regimens in three critically ill children. Ceftolozane pharmacokinetics (PK) were characterized by obtaining the patient’s specific parameters by Bayesian estimation based on a population PK model. The clearance (CL) in patient C undergoing CRRT was estimated using the prefilter, postfilter, and ultrafiltrate concentrations simultaneously. Variables such as blood, dialysate, replacement, and ultrafiltrate flow rates, and hematocrit were integrated in the model. All PK analyses were performed using NONMEM v.7.4. Results: Patient A (8 months of age, 8.7 kg) with normal renal function received 40 mg/kg every 6 h: renal clearance (CL_R) was 0.88 L/h; volume of distribution (Vd) Vd₁ = 3.45 L, Vd₂ = 0.942 L; terminal halflife (t_1/2,β) = 3.51 h, dosing interval area under the drug concentration vs. time curve at steady-state (AUC_τ,SS) 397.73 mg × h × L⁻¹. Patient B (19 months of age, 11 kg) with eGFR of 22 mL/min/1.73 m² received 36 mg/kg every 8 h: CL_R = 0.27 L/h; Vd₁ = 1.13 L; Vd₂ = 1.36; t_1/2,β = 6.62 h; AUC_SS 1481.48 mg × h × L⁻¹. Patient C (9 months of age, 5.8 kg), with severe renal impairment undergoing CRRT received 30 mg/kg every 8 h: renal replacement therapy clearance (CL_RRT) 0.39 L/h; Vd_{1 =} 0.74 L; Vd₂₌ 1.17; t _{1/2,β =} 3.51 h; AUC_τ,SS 448.72 mg × h × L⁻¹. No adverse effects attributable to antibiotic treatment were observed. Conclusions: Our results suggest that a dose of 35 mg/kg every 8 h can be appropriate in critically ill septic children with multi-drug resistance Pseudomonas aeruginosa infections. A lower dose of 10 mg/kg every 8 h could be considered for children with severe AKI. For patients with CRRT and a high effluent rate, a dose of 30 mg/kg every 8 h can be considered. Full article