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International Journal of Infectious... Jun 2024Evaluate and compare the efficacy and safety of molnupiravir and favipiravir in outpatients with mild to moderate COVID-19 and at risk of severe COVID-19. (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
OBJECTIVES
Evaluate and compare the efficacy and safety of molnupiravir and favipiravir in outpatients with mild to moderate COVID-19 and at risk of severe COVID-19.
METHODS
In an open-label, parallel-group, multicenter trial in Thailand, participants with moderate COVID-19 and at least one factor associated with severe COVID-19 were randomly assigned 1:1 to receive oral molnupiravir or oral favipiravir (standard of care). Phone calls for remote symptom assessment were made on Days 6, 15, and 29. Participants with worsening symptoms were instructed to return to the hospital. The primary endpoint was pulmonary involvement by Day 29, as evidenced by ≥2 of the following: dyspnea, oxygen saturation <92% or imaging.
RESULTS
Nine hundred seventy-seven participants (487 molnupiravir, 490 favipiravir) were enrolled from 8 July 2022 to 19 January 2023. 98% had received ≥1 dose of COVID-19 vaccine and 83% ≥3 doses. By Day 29, pulmonary involvement occurred in 0% (0/483) in molnupiravir arm versus 1% (5/482) in favipiravir arm (-1.0%; Newcombe 95.2% CI: -2.4% to -0.0%; P = 0.021); all-cause death in 0% (0/483) and <1% (1/482); COVID-19 related hospitalization in <1% (1/483) and 1% (3/482); treatment-related adverse event in 1% (5/483) and 1% (4/486); and serious adverse event in 1% (4/483) and 1% (4/486).
CONCLUSIONS
Favipiravir and molnupiravir had a similar efficacy and safety profile. Whether either of the two reduced the risk of complications during the omicron era in this population with a low risk of pulmonary involvement and a high vaccine coverage remains unclear. There were no differences in any of the safety endpoints.
THAI CLINICAL TRIALS REGISTRY ID
TCTR20230111009.
Topics: Humans; Amides; Male; Pyrazines; Female; Thailand; COVID-19 Drug Treatment; Antiviral Agents; Middle Aged; SARS-CoV-2; Adult; Cytidine; Hydroxylamines; Aged; Treatment Outcome; COVID-19; Outpatients
PubMed: 38561040
DOI: 10.1016/j.ijid.2024.107021 -
Nature Communications Mar 2024Potential synergism between Bruton's tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report...
Potential synergism between Bruton's tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab (R2A) in patients with aggressive relapsed/refractory aggressive (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint of this study is objective response rate (ORR), and the secondary endpoints are complete remission (CR) rate, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). A total of 66 patients are enrolled mostly with diffuse large B-cell lymphoma. The ORR is 54.5% and CR rate is 31.8% meeting the primary end point. The median DoR is 12.9 months, and 1-year PFS and OS rate is 33.1% and 67.5% respectively. Adverse events (AE) are manageable with the most frequent AE being neutropenia (31.8%). Patients with MYD88 mutations, subtypes known for NF-κB activation, and high BTK expression by immunohistochemistry respond well. Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142).
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Lenalidomide; Lymphoma, Large B-Cell, Diffuse; Pyrazines; Rituximab; Treatment Outcome
PubMed: 38555311
DOI: 10.1038/s41467-024-47198-4 -
Nature Communications Mar 2024The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian...
The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.
Topics: Female; Humans; BRCA1 Protein; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Pyrazoles; Protein Kinase Inhibitors; Neoplasm Recurrence, Local; Antineoplastic Combined Chemotherapy Protocols; Chromosomal Proteins, Non-Histone; Pyrazines
PubMed: 38555285
DOI: 10.1038/s41467-024-47215-6 -
Experimental Physiology May 2024It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the...
It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and , and renal function were then monitored for up to 8 h post-treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.
Topics: Animals; Furosemide; Acetazolamide; Amiloride; Diuretics; Sheep; Female; Kidney Cortex; Kidney Medulla; Oxygen; Hemodynamics; Oxygen Consumption
PubMed: 38551893
DOI: 10.1113/EP091479 -
Mathematical Biosciences and... Feb 2024Bortezomib and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts protein degradation in cells, leading to...
Bortezomib and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts protein degradation in cells, leading to the accumulation of unfolded proteins that induce apoptosis. On the other hand, virotherapy uses genetically modified oncolytic viruses (OVs) to infect cancer cells, trigger cell lysis, and activate anti-tumor response. Despite progress in cancer treatment, identifying administration protocols for therapeutic agents remains a significant concern, aiming to strike a balance between efficacy, minimizing toxicity, and administrative costs. In this work, optimal control theory was employed to design a cost-effective and efficient co-administration protocols for bortezomib and OVs that could significantly diminish the population of cancer cells via the cell death program with the NF$ \kappa $B-BAX-RIP1 signaling network. Both linear and quadratic control strategies were explored to obtain practical treatment approaches by adapting necroptosis protocols to efficient cell death programs. Our findings demonstrated that a combination therapy commencing with the administration of OVs followed by bortezomib infusions yields an effective tumor-killing outcome. These results could provide valuable guidance for the development of clinical administration protocols in cancer treatment.
Topics: Humans; Bortezomib; Oncolytic Virotherapy; Oncolytic Viruses; Neoplasms; Cell Death
PubMed: 38549312
DOI: 10.3934/mbe.2024173 -
Scientific Reports Mar 2024Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA....
Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA. Hesperidin and sitagliptin were investigated for their antioxidant, anti-inflammatory, and tissue-protective properties. We aimed to investigate and compare the possible nephroprotective effects of hesperidin and sitagliptin. Male Wistar rats were utilized for induction of CsA nephrotoxicity (20 mg/kg/day, intraperitoneally for 7 days). Animals were treated with sitagliptin (10 mg/kg/day, orally for 14 days) or hesperidin (200 mg/kg/day, orally for 14 days). Blood urea, serum creatinine, albumin, cystatin-C (CYS-C), myeloperoxidase (MPO), and glucose were measured. The renal malondialdehyde (MDA), glutathione (GSH), catalase, and SOD were estimated. Renal TNF-α protein expression was evaluated. Histopathological examination and immunostaining study of Bax, Nrf-2, and NF-κB were performed. Sitagliptin or hesperidin attenuated CsA-mediated elevations of blood urea, serum creatinine, CYS-C, glucose, renal MDA, and MPO, and preserved the serum albumin, renal catalase, SOD, and GSH. They reduced the expressions of TNF-α, Bax, NF-κB, and pathological kidney damage. Nrf2 expression in the kidney was raised. Hesperidin or sitagliptin could protect the kidney against CsA through the mitigation of oxidative stress, apoptosis, and inflammation. Sitagliptin proved to be more beneficial than hesperidin.
Topics: Rats; Animals; Male; Cyclosporine; NF-kappa B; Catalase; Tumor Necrosis Factor-alpha; bcl-2-Associated X Protein; Hesperidin; NF-E2-Related Factor 2; Rats, Wistar; Sitagliptin Phosphate; Creatinine; Kidney Diseases; Kidney; Oxidative Stress; Renal Insufficiency; Glutathione; Urea; Superoxide Dismutase; Glucose
PubMed: 38548778
DOI: 10.1038/s41598-024-57300-x -
Current Problems in Cancer Jun 2024This retrospective longitudinal study compared the effectiveness of dexamethasone+lenalidomide (Rd)-based triplet regimens containing proteasome inhibitors (PIs)... (Comparative Study)
Comparative Study
Comparative effectiveness of lenalidomide/dexamethasone-based triplet regimens for treatment of relapsed and/or refractory multiple myeloma in the United States: An analysis of real-world electronic health records data.
BACKGROUND
This retrospective longitudinal study compared the effectiveness of dexamethasone+lenalidomide (Rd)-based triplet regimens containing proteasome inhibitors (PIs) ixazomib (IRd), carfilzomib (KRd), and bortezomib (VRd) or monoclonal antibodies (MABs) elotuzumab (ERd) and daratumumab (DRd) in patients with relapsed/refractory multiple myeloma (RRMM)-including those with high cytogenetic risk-primarily treated at community oncology clinics in the United States.
METHODS
Electronic health records of adult RRMM patients in a deidentified real-world database (01/01/2014-09/30/2020) who initiated IRd, KRd, VRd, ERd, or DRd in the second or later line of therapy (LOT) were analyzed. The index date was the date of initiation of each LOT and baseline was the 6-month pre-index period. Duration of therapy (DOT), time to next therapy (TTNT), progression-free survival (PFS), and overall survival (OS) were compared across regimens with multivariable Cox proportional hazards models.
RESULTS
Of the 1,185 patients contributing 1,332 LOTs, 985 had standard cytogenetic risk (median age, 71 years) and 180 had high risk (median age, 69 years). Compared with other regimens, DRd was associated with longer DOT overall (adjusted hazard ratio [95 % confidence interval]: 1.84 [1.42, 2.38] vs. KRd, 1.65 [1.20, 2.28] vs. ERd, 1.58 [1.23, 2.04] vs. IRd, and 1.54 [1.18, 2.00] vs. VRd), and longer TTNT and PFS. KRd was associated with shorter OS compared with DRd (1.45 [1.01, 2.08]) and VRd (1.32 [1.01, 1.73]). High-risk patients had similar outcomes with all triplet regimens.
CONCLUSION
Although DRd improved clinical outcomes overall, Rd-based triplet regimens containing a PI or MAB are similarly effective in high-risk RRMM.
Topics: Humans; Multiple Myeloma; Male; Female; Dexamethasone; Aged; Antineoplastic Combined Chemotherapy Protocols; Lenalidomide; Retrospective Studies; Middle Aged; United States; Electronic Health Records; Boron Compounds; Oligopeptides; Neoplasm Recurrence, Local; Longitudinal Studies; Bortezomib; Glycine; Antibodies, Monoclonal, Humanized; Aged, 80 and over; Survival Rate; Follow-Up Studies; Antibodies, Monoclonal
PubMed: 38547609
DOI: 10.1016/j.currproblcancer.2024.101078 -
European Journal of Clinical... Jul 2024Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal...
PURPOSE
Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CL) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail.
METHODS
Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination.
RESULTS
A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h vs. 5.18 h) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (K) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (V) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min.
CONCLUSION
The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high K value suggests that assessing renal OAT1 activity by CL has no relevant misspecification error with the cocktail doses used.
Topics: Humans; Organophosphonates; Adenine; Male; Adult; Models, Biological; Female; Organic Anion Transport Protein 1; Drug Interactions; Phenotype; Middle Aged; Young Adult; Digoxin; Metformin; Sitagliptin Phosphate; Biological Availability
PubMed: 38546841
DOI: 10.1007/s00228-024-03673-x -
Haematologica Jul 2024
Efficacy and safety of daratumumab plus bortezomib and dexamethasone in newly diagnosed Mayo 2004 stage IIIA or IIIB light-chain amyloidosis: a prospective phase II study.
Topics: Humans; Bortezomib; Dexamethasone; Immunoglobulin Light-chain Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal; Male; Female; Prospective Studies; Aged; Treatment Outcome; Middle Aged; Neoplasm Staging
PubMed: 38546676
DOI: 10.3324/haematol.2024.285145 -
Asian Pacific Journal of Cancer... Mar 2024Multiple myeloma (MM), being the second most common hematological malignancy, has garnered significant attention. The ubiquitin proteasomal pathway (UPP), crucial for...
BACKGROUND
Multiple myeloma (MM), being the second most common hematological malignancy, has garnered significant attention. The ubiquitin proteasomal pathway (UPP), crucial for normal cell function, plays a pivotal role in myeloma pathophysiology, especially with the advent of bortezomib (BTZ). Dysregulation of the UPP has implications ranging from developmental abnormalities to cancer.
OBJECTIVES
This study aimed to delineate the clinical characteristics of newly diagnosed multiple myeloma patients and investigate the influence of single nucleotide polymorphisms (SNPs) in NF-ĸB2 and TRAF3 genes on the risk and treatment response to bortezomib-based chemotherapy.
MATERIALS AND METHODS
Conducted at JIPMER, Pondicherry, this prospective study enrolled 184 participants, comprising cases and controls. DNA extraction from peripheral blood samples was followed by SNP analysis through Real-time Polymerase Chain Reaction. Patients were categorized into Good and Poor responders, and SNP associations with treatment response, response rates, and survival outcomes were assessed using chi-square and Kaplan-Meier analyses.
RESULTS
The median age of participants was 55 years, with backache being the most prevalent symptom (66.3%). Hypercalcemia (22%), renal failure (8.7%), and bone fractures (45.7%) were also observed, alongside high prevalence of anemia. Notably, the frequency of the TRAF3 rs12147254 A allele was lower in cases compared to controls (31% vs. 49%, P-value=0.002). Poor responders exhibited higher frequencies of the GA+AA genotypes in TRAF3 rs12147254 (OR-3.882(1.629-9.251), P-value-0.002) and NFKB2 rs1056890 (OR-3.308(1.366-8.012), P-value-0.008) when compared to good responders. The GA+AA genotype in TRAF3 rs11160707 SNP correlated with improved progression-free survival.
CONCLUSION
The study findings underscore a significant association between genetic polymorphisms and treatment response outcomes, suggesting their utility in prognostic determinations and clinical outcomes prediction in multiple myeloma patients.
Topics: Humans; Middle Aged; Bortezomib; Multiple Myeloma; TNF Receptor-Associated Factor 3; Prospective Studies; Polymorphism, Single Nucleotide; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38546066
DOI: 10.31557/APJCP.2024.25.3.829