Role of HDL cholesterol in anthracycline-induced subclinical cardiotoxicity: a prospective observational study in patients with diffuse large B-cell lymphoma treated with R-CHOP.

OBJECTIVES: Anthracycline-induced cardiotoxicity is a debilitating cardiac dysfunction for which there are no effective treatments, making early prevention of anthracycline-induced subclinical cardiotoxicity (AISC) crucial. High-density lipoprotein cholesterol (HDL-C) plays a role in cardioprotection, but its impact on AISC remains unclear. Our study aims to elucidate the protective capacity of HDL-C in AISC in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone and rituximab). DESIGN: Prospective observational study. SETTING: Conducted in China from September 2020 to September 2022. PARTICIPANTS: 70 chemotherapy-naïve patients newly diagnosed with DLBCL who were scheduled to receive the standard dose of R-CHOP; 60 participants included in a case-control study (DOI: 10.1186/s12885-022-10085-6). PRIMARY OUTCOME MEASURES: Serum biomarkers, 2D speckle tracking echocardiography and conventional echocardiography were measured at baseline, at the end of the third and sixth cycles of R-CHOP and 6 and 12 months after chemotherapy. RESULTS: 24 patients experienced AISC, while 10 did not. 36 patients were lost to follow-up and death. Cox regression analysis showed that higher levels of HDL-C were associated with a significantly lower risk of AISC (unadjusted HR=0.24, 95% CI 0.09 to 0.67, p=0.006; adjusted HR=0.27, 95% CI 0.09 to 0.79, p=0.017). Patients without AISC had a more stable and higher HDL-C level during the follow-up period. HDL-C levels significantly decreased from the end of the third cycle of chemotherapy to the end of the sixth cycle of chemotherapy in all patients (p=0.034), and particularly in the AISC group (p=0.003). The highest level of HDL-C was significantly higher in patients without AISC than in those with AISC (1.52±0.49 vs 1.22±0.29, p=0.034). CONCLUSIONS: Our study suggests that higher HDL-C levels may associate with lower AISC risk in patients with DLBCL treated with R-CHOP. HDL-C could be a cardioprotective target, but further research is needed to confirm its benefits and limitations. STUDY REGISTRATION NUMBER: Study registration number: ChiCTR2100054721.

A new pregnane glycoside and oligosaccharide from Parabarium huaitingii.

Two new compounds, along with two known compounds, were isolated from the barks of Parabarium huaitingii, and their structures were determined as 5α-pregn-6-ene-3ß,17α,20(S)-triol-20-O-ß-d-digitoxopyranoside (1), cymaropyranurolactone 4-O-ß-d-digitalopyranosyl-(1 â†’ 4)-O-ß-d-cymaropyranosyl-(1 â†’ 4)-O-ß-d-oleandropyranosyl-(1 â†’ 4)-O-ß-d-cymaropyranoside (2), 3ß,17α,20(S)-trihydroxy-5α-pregn-6-ene (3), and 5α-pregn-6-ene-3ß,17α,20(S)-triol-3-O-ß-d-digitalopyranoside (4) by spectroscopic methods.

Inhibitory effect of Adonis amurensis components on tube-like formation of human umbilical venous cells.

Antiangiogenic activity-guided fractionation and isolation carried out on the methanol extract of Adonis amurensis led to the identification of three compounds, namely cymarin, cymarol, and cymarilic acid. Amongst the three compounds, cymarilic acid was isolated from this plant for the first time. This compound showed no significant cytotoxicity against tumor cell lines but was found to be strongly inhibitory toward tube formation induced by human umbilical venous endothelial (HUVE) cells. Cymarin and cymarol exhibited potent cytotoxicity against a human solid tumor cell line A549 (human lung carcinoma), while being inactive on murine leukemic cells (L1210).

Preparation and evaluation of technetium-99m labeled cardiac glycoside derivatives as potential myocardial imaging agent.

Three cardiac glycosides, two natural, cymarin and convallotoxin and one synthetic, strophanthidin-beta-D-glucoside were converted to their thiosemicarbazone and subsequently radiolabeled with 99mTc by chelation. The resulting radioactive chelate complexes were evaluated in animals to determine the suitability of this class of compounds for myocardial imaging. It was observed from the animal biodistribution data of the three radioactive compounds, there was a considerable variation in the heart to non-target organ uptake ratio. A possible explanation of this variation was offered in the light of their lipophilic character, protein binding ability and affinity towards non-target receptors. It is anticipated that this study may help to develop a 99mTc-cardiac glycoside complex with better distribution characteristics, and such a compound may offer a suitable alternative to 201Tl, which is at present used for myocardial imaging.

Photoaffinity labeling of (Na+K+)-ATPase with [125I]iodoazidocymarin.

A radioiodinated, photoactive cardiac glycoside derivative, 4'-(3-iodo-4-azidobenzene sulfonyl)cymarin (IAC) was synthesized and used to label (Na+K+)-ATPase in crude membrane fractions. In the dark, IAC inhibited the activity of (Na+K+)-ATPase in electroplax microsomes from Electrophorus electricus with the same I50 as cymarin. [125I]IAC binding, in the presence of Mg2+ and Pi, was specific, of high affinity (KD = 0.4 microM), and reversible (k-1 = 0.11 min-1) at 30 degrees C. At 0 degree C, the complex was stable for at least 3 h, thus permitting washing before photolysis. Analysis of [125]IAC photolabeled electroplax microsomes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) (7-14%) showed that most of the incorporated radioactivity was associated with the alpha (Mr = 98,000) and beta (Mr = 44,000) subunits of the (Na+K+)-ATPase (ratio of alpha to beta labeling = 2.5). A higher molecular weight peptide (100,000), similar in molecular weight to the brain alpha(+) subunit, and two lower molecular weight peptides (12,000-15,000), which may be proteolipid, were also labeled. Two-dimensional gel electrophoresis (isoelectric focusing then SDS-PAGE, 10%) resolved the beta subunit into 12 labeled peptides ranging in pI from 4.3 to 5.5. When (Na+K+)-ATPase in synaptosomes from monkey brain cortex was photolabeled and analyzed by SDS-PAGE (7-14%), specific labeling of the alpha(+), alpha, and beta subunits could be detected (ratio of alpha(+) plus alpha to beta labeling = 35). The results show that [125I]IAC is a sensitive probe of the cardiac glycoside binding site of (Na+K+)-ATPase and can be used to detect the presence of the alpha(+) subunit in crude membrane fractions from various sources.

3H-Cymarol in man. Excretion pathways and serum protein binding.

In 10 patients, 5 having received 3H-cymarol i.v., 5 orally, the radioactivity in plasma, urine and in the feces of some patients also was determined. After oral administration the plasma levels rose rapidly reaching maximum levels 1--2 h after administration. After i.v. injection about 30% of the given radioactivity were excreted in the urine. The remaining radioactivity was found in the feces suggesting a high biliary excretion. Only 10% of the radioactivity excreted in the first 24 h were chloroform-extractable. The radioactivity found in the urine after oral administration of the drug amounted to 17.6%. Between 51.1 and 58.5% of the drug were bound to serum proteins.

Cardenolide analogues. VI. The metabolism of the prodrug diacetylcymarol in the rat.

1. Diacetylcymarol is an acetylated glycoside which is better absorbed than the parent glycoside, cymarol. 2. Diacetyl[19-3H]cymarol was rapidly metabolized and excreted by the rat following intraperitoneal administration. 3. The drug was metabolized extensively to polar compounds with the principal pathway involving loss of the C-19 acetyl group and probable demethylation of the sugar. 4. The bulk of the radioactive material was excreted in the bile and there was little reabsorption. 5. The results show that acetylation was successful in converting the poorly absorbed glycoside, cymarol, into a derivative that was rapidly absorbed from the peritoneal cavity. 6. Following or during absorption, the biologically inactive diacetylcymarol was converted to polar derivatives with potential therapeutic activity. However, subsequent elimination was so rapid that little therapeutic benefit could be expected.