Razoxane 125mg tablets

Valvular heart disease (VHD) is a common cardiovascular disorder with insidious early symptoms and can progress to heart failure or sudden death. Pharmacological options remain limited, and severe disease often requires surgical intervention. This study aimed to identify key molecular targets and potential therapeutic candidates for VHD using Mendelian randomization (MR) and integrative analyses. A 2-sample MR design was used to evaluate the association between genetically predicted exposures and VHD using publicly available genome-wide association study summary statistics. Downstream analyses included functional enrichment, drug repurposing with molecular docking, protein-protein interaction network construction with hub-gene identification, and single-cell RNA sequencing-based analysis to examine the cell-type distribution of candidate gene expression. MR analysis identified 76 genes associated with VHD, including stathmin 1, ribosomal protein S5, and mitogen-activated protein kinase 8. Enrichment analysis suggested that these genes were involved in multiple signaling pathways potentially related to disease progression. Drug prediction and molecular docking prioritized razoxane, reserpine, and bisindolylmaleimide I as candidate compounds targeting key molecules. Protein-protein interaction network analysis further identified 10 hub genes, such as DEAD-box helicase 6 and apolipoprotein E. Single-cell sequencing showed high expression of these genes in cardiomyocytes, fibroblasts, and smooth muscle cells. This study identified candidate genes and potential drug leads for VHD through an MR-based integrative analysis, providing targets for subsequent mechanistic and experimental validation.

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<title>Abstract</title> Background The global call for malaria eradication rested on finding drugs that not only act against asexual but also sexual forms of the parasite. The drawbacks in disease control and prevention due to drug-resistant clones of the parasite piqued our interest in exploring for alternative antimalarial drugs from the mangrove resources. Aims This study evaluates the stage-specific anti-malarial and cytotoxic activities of the fractions of crude alkaloidal extracts from <italic>Avicennia africana</italic> leaves. Methods The crude and alkaloidal extracts (AAA and AAQ) from <italic>A. africana</italic> were fractionated using column chromatography and further analysed using GC-mass spectroscopy. The fractions were then tested for antimalarial activity against the trophozoites, schizonts, and gametocyte stages of chloroquine-sensitive strains of 3D7 <italic>P. falciparum</italic> using the SYBR Green 1 assay. The cytotoxic effects of the fractions were evaluated using the MTT-based assay. Results The fractions AAA1-AAA5 and AAQ1-AAQ5 produced promising trophozoitocidal activities with an IC₅₀ value range of 0.399–45.690 µg/mL, with the artesunate (ref drug) yielding 0.09x10³ µg/mL. The schizonticidal and gametocytocidal activities of selected fractions demonstrated high potency with IC_50s of 0.622–18.820 µg/mL against artesunate (ref drugs) with 1.800x10^-3 and 5.100x10^-3 µg/mL, respectively. The cytotoxic effect of fractions produced CC₅₀ that was higher than 100 µg/mL with negligible cytotoxicity on erythrocytes and SI that ranged from 2.189 to 280.899. The major compounds identified in fractions AAA1, AAQ1, and AAQ2 were 8-carbomoylquinoline, razoxane, and dexrazoxane, respectively. Conclusion The fractions exhibited promising trophozoitocidal, schizonticidal, and gametocytocidal effects with no significant cytotoxic effects on RBCs. Quinoline-based alkaloids and iron chelators in this plant are implicated as possible lead-compound transmission blockers of the parasite.

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Measurement of tumour and normal tissue perfusion in vivo in cancer patients will aid the clinical development of antiangiogenic and antivascular agents. We investigated the potential antiangiogenic effects of the drug razoxane by measuring the changes in parameters estimated from H(2)(15)O and C(15)O positron emission tomography (PET) to indicate alterations in vascular physiology. The study comprised 12 patients with primary or metastatic renal tumours >3 cm in diameter enrolled in a Phase II clinical trial of oral razoxane. Perfusion, fractional volume of distribution of water (VD) and blood volume (BV) were measured in tumour and normal tissue before and 4-8 weeks after treatment with 125 mg twice-daily razoxane. Renal tumour perfusion was variable but lower than normal tissue: mean 0.87 ml min(-1) ml(-1) (range 0.33-1.67) compared to renal parenchyma: mean 1.65 ml min(-1) ml(-1) (range 1.16-2.88). In eight patients, where parallel measurements were made during the same scan session, renal tumour perfusion was significantly lower than in normal kidney (P=0.0027). There was no statistically significant relationship between pretreatment perfusion and tumour size (r=0.32, n=13). In six patients scanned before and after razoxane administration, there was no statistically significant change in tumour perfusion: mean perfusion pretreatment was 0.81 ml min(-1) ml(-1) (range 0.46-1.26) and perfusion post-treatment was 0.72 ml min(-1) ml(-1) (range 0.51-1.15, P=0.15). Tumour VD and BV did not change significantly following treatment: mean pretreatment VD=0.66 (range 0.50-0.87), post-treatment VD=0.71 (range 0.63-0.82, P=0.22); pretreatment BV=0.18 ml ml(-1) (range 0.10-0.25), post-treatment BV=0.167 ml ml(-1) (range 0.091-0.24, P=0.55). Tumour perfusion, VD and BV did not change significantly with tumour progression. This study has shown that H(2)(15)O and C(15)O PET provide useful in vivo physiological measurements, that even highly angiogenic renal cancers have poor perfusion compared to surrounding normal tissue, and that PET can provide valuable information on the in vivo biology of angiogenesis in man and can assess the effects of antiangiogenic therapy.

Abstract licence: CC BY-NC-SA