Multiple dose kinetics of spironolactone and canrenoate-potassium in cardiac and hepatic failure

Summary Plasma concentrations of canrenone and canrenoate were measured in 43 patients treated with spironolactone 50–400 mg/day, and in one patient treated with canrenoate-K 3×200 mg/day. The cumulation of canrenone and canrenoate was followed in 9 patients recovering from myocardial infarction, without congestive heart failure or cirrhosis, who received spironolactone 2×100 mg/day. The cumulation half-life was 1–4 days, which may partly explain the delayed clinical action of spironolactone. The plasma elimination half-life of canrenone and canrenoate in six of these patients lay between 13.5 and 24 h. After 10 doses it was unchanged in three patients and had decreased only slightly in three others. Steady state minimum plasma levels of canrenone and canrenoate were measured in 33 patients with congestive heart failure or cirrhosis who received spironolactone 50–400 mg/day for at least three weeks. There was up to 15 fold inter-individual variation in the plasma levels of canrenone amongst those receiving spironolactone 200 mg/day. No statistically significant correlation was found between steady state levels of canrenone and plasma creatinine or the results of bromsulphalein liver function tests. In one patient with severe congestive heart failure given canrenoate-K 3×200 mg/day, cumulation of canrenone and canrenoate occurred for seven days, followed by a gradual decline in their plasma levels until the eleventh day of therapy. A loading dose is recommended for initiation of spironolactone therapy.     

The treatment of subglottic hemangiomas of infants with prednisone

Because of their spontaneous regression, capillary and cavernous hemangiomas of infants usually do not require treatment. However, when they interfere because of their location with important functions of the body or even threaten life, treatment becomes mandatory. This is the case in most patients with congenital subglottic hemangiomas. In the past various methods of treatment have been used. All of them have disadvantages, and some are hazardous. Most cases (74.2%) required protracted tracheostomy. Mortality rate is still high (23.8%).We report herewith 5 infants with subglottic hemangiomas successfully treated with prednisone. No remarkable side-effects were observed, besides transient moonfacing. Similar good results were previously reported in 9 cases by several authors. Prednisone therapy if instituted early may reduce the need of tracheostomy and bring about complete recovery in this sometimes severe condition. Proper dosage and sufficient length of treatment are absolutely essential for such successful outcome.     

Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells

Membrane transporters play important roles in mediating chemosensitivity and -resistance of tumor cells. ABC transporters, such as ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP, are frequently associated with decreased cellular accumulation of anticancer drugs and multidrug resistance of tumors. SLC transporters, such as folate, nucleoside, and amino acid transporters, commonly increase chemosensitivity by mediating the cellular uptake of hydrophilic drugs. Ion channels and pumps variably affect sensitivity to anticancer therapy by modulating viability of tumor cells. A pharmacogenomic approach, using correlations between drug potency and transporter gene expression in multiple cancer cell lines, has shown promise for identifying potential drug-transporter relationships and predicting anticancer drug response, in an effort to optimize chemotherapy for individual patients.     

Prediction of anticancer drug potency from expression of genes involved in growth factor signaling

Purpose This study develops and evaluates a systematic approach to finding biomarker genes for predicting potency of anticancer drugs against tumor cells, focusing on gene families related to growth factor signaling. Methods Cytotoxic potencies of 119 drugs against 60 neoplastic cell lines (NCI-60) were correlated with expression of 343 genes, including 90 growth factors and receptors, 63 metalloproteinases, and 92 ras-like GTPases as downstream signaling factors. Progressively more stringent criteria and predictive models aim at identifying the smallest subset of genes predictive of cytotoxic potency. Results Comparing gene expression with drug potency across the NCI-60 yielded genes with negative and positive correlations (p < 0.001), indicative of a role in chemoresistance and chemosensitivity, respectively. Of 17 genes with multiple negative correlations, 8 are known chemoresistance factors, validating the approach. Negatively correlated genes clustered into two main groups with distinct expression profiles and drug correlations, represented by EGFR and ERBB2 (Her-2/Neu). Accordingly, no synergism was observed between EGFR and ERBB2 inhibitors. However, combinations with classical anticacer drugs were not correlated with EGFR and ERBB2 expression in four cell lines tested, suggesting complex interactions in combination treatments. Finally, a subset of only 13 genes was found to be sufficient for near optimal prediction of drug potency against the NCI-60. Conclusions Our approach using a small subset of genes reveals known and potential biomarkers in cancer chemotherapy, providing a strategy for genome-wide analysis. Electronic Supplementary Material Supplementary material to this paper is available in electronic form at