Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply.

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.

Direct Pulmonary Vein Ablation With Stenosis Prevention Therapy.

INTRODUCTION: The dominant location of electrical triggers for initiating atrial fibrillation (AF) originates from the muscle sleeves inside pulmonary veins (PVs). Currently, radiofrequency ablation (RFA) is performed outside of the PVs to isolate, rather than directly ablate these tissues, due to the risk of intraluminal PV stenosis. METHODS: In 4 chronic canine experiments, we performed direct PV muscle sleeve RFA ± postablation drug-coated balloon (DCB) treatment with paclitaxel/everolimus. Of the 4 PVs, 2 PVs were ablated and treated with DCB, 1 PV was ablated without DCB treatment (positive control), and 1 PV was left as a negative control. Local electrograms were assessed in PVs for near-field signals and were targeted for ablation. After 12-14 weeks survival, PVs were interrogated for absence of near-field PV potentials, and each PV was assessed for stenosis. RESULTS: All canines survived the study period without cardiorespiratory complications, and remained ambulatory. In all canines, PVs that were ablated and treated with DCB remained without any significant intraluminal stenosis. In contrast, PVs that were ablated and not treated with DCB showed near or complete intraluminal stenosis. At terminal study, PV potentials remained undetectable. A blinded, histologic analysis demonstrated that ablated PVs without DCB treatment had extensive thrombus, fibrin, mineralization, and elastin disruption. CONCLUSION: Our chronic canine data suggest that direct PV tissue ablation without subsequent stenosis is feasible with the use of postablation DCBs.

Induction of apoptosis in human cervical carcinoma HeLa cells by active compounds from Hypericum ascyron L.

Hypericum ascyron L. (Great St. Johnswort), which belongs to the Hypericaceae family, has been used for the treatment of hematemesis, metrorrhagia, rheumatism, swelling, stomach ache, abscesses, dysentery and irregular menstruation for >2,000 years in China. The aim of the present study was to clarify the anticancer activity compounds from H. ascyron L. and the underlying molecular mechanism. Anticancer activity of H. ascyron L. extract was evaluated using an MTT assay. To confirm the anticancer mechanism of activity compounds, Hoechst 33258, Annexin V-fluorescein isothiocyanate/propidium iodide, 2',7'-dichlorodihydrofluorescein diacetate, rhodamine 123 staining and caspase-3 activity analysis were performed. The results demonstrated that the anti-proliferative action of the mixture of kaempferol 3-O-ß-(2″-acetyl) galactopyranoside (K) and quercetin (Q) (molar ratio, 1:1) was significantly increased compared with either of these two compounds separately, and the active fraction of the H. ascyron L. extract |(HALE). HALE, indicating that the anti-proliferative function of H. ascyron L. may be a synergic effect of K and Q. Furthermore, the inhibitory effect of KQ on the growth of HeLa cells was mediated by the induction of apoptosis. To the best of our knowledge, the present study is the first to identify that KQ exhibits significant anti-proliferation activity on HeLa cells via the apoptotic pathway, and is also the first to evaluate the anticancer potential of H. ascyron L. The results of the present study may provide a rational base for the use of H. ascyron L. in the clinic, and shed light on the development of novel anticancer drugs.

RP5063, a novel, multimodal, serotonin receptor modulator, prevents Sugen 5416-hypoxia-induced pulmonary arterial hypertension in rats.

RP5063, a multimodal dopamine (DA) and serotonin (5-HT) modulator with high affinity for DA2/3/4 and 5-HT2A/2B/7 receptors and moderate affinity for SERT, is a novel therapeutic of special interest in the treatment of pulmonary arterial hypertension (PAH). Evidence indicates that therapeutics targeting the 5-HT2A/2B receptors can influence the pathogenesis of PAH. However, the therapeutic effect of RP5063 in humans has yet to be investigated. A Sugen 5416-hypoxia (SuHx)-induced PAH model was used to evaluate twice-daily (b.i.d.) RP5063 at 10mg/kg (RP-10) and 20mg/kg (RP-20), as compared with positive (sildenafil 50mg/kg b.i.d.; Sil-50) and negative controls (SuHx+vehicle; SuHx+veh), in 24 adult male Wistar-Kyoto rats. RP5063 showed significantly lower systolic pulmonary arterial (both doses) and systolic right ventricular (RP-10) pressures, and improvement in oxygen saturation (RP-20). It significantly reduced small-vessel wall thickness (RP-20), lowered the percentage of muscular vessels (both doses). Both doses limited arterial obliteration due to endothelial cell proliferation, prevented plexiform lesion formation, and stemmed the release of leukotriene B4. Sildenafil showed statistically greater effects on vessel structure than that seen in both RP5063 groups and improved oxygen saturation. Additionally, Sildenafil did not demonstrate any significant effect on arterial obliteration, plexiform lesion development, or pulmonary arterial or right ventricular pressure. As PAH gains in severity, the impact of RP5063 inhibition of 5HT2B increases, preventing arterial constriction and improving pulmonary hemodynamics. Due to its functional, structural, and chemokine effects, RP5063 represents a promising candidate for investigation in late-phase PAH.

Novel alkylphospholipid-DTC hybrids as promising agents against endocrine related cancers acting via modulation of Akt-pathway.

A new series of 2-(alkoxy(hydroxy)phosphoryloxy)ethyl dialkylcarbodithioate derivatives was synthesized and evaluated against endocrine related cancers, acting via modulation of Akt-pathway. Eighteen compounds were active at 7.24-100 µM against MDA-MB-231 or MCF-7 cell lines of breast cancer. Three compounds (14, 18 and 22) were active against MCF-7 cells at IC50 significantly better than miltefosine and most of the compounds were less toxic towards non-cancer cell lines, HEK-293. On the other hand, twelve compounds exhibited cell growth inhibiting activity against prostate cancer cell lines, either PC-3 or DU-145 at 14.69-95.20 µM. While nine of these were active against both cell lines. The most promising compounds 14 and 18 were about two and five fold more active than miltefosine against DU-145 and MCF-7 cell lines respectively and significantly down regulated phospho-Akt. Possibly anti-cancer and pro-apoptotic activity was mostly due to blockade of Akt-pathway.

The Expression of Insulin-like Growth Factor (IGF), IGF- Binding Protein (IGFBP) and the Role of IGFBP-3 in the Korean Gastric Cancer Cell Lines / 대한암학회지

PURPOSE: Insulin-like growth factor (IGF)-I and II are potent mitogens, postulated to exert autocrine and paracrine effects on growth regulation in human gastric cancer. In this study, we evaluated the expression of IGF-I, -II and IGFBPs in a panel of human gastric cancer cell lines. We also evaluated whether high expression of IGFBP-3 in human gastric cancer cells may increase the sensitivity to the anti-proliferative agents. MATERIALS AND METHODS: 10 human korean gastric cancer ceIl lines and 1 Caucacian gastric adenocarcinoma cell line were used for this study. IGF and IGFBP expressions were evaluated by RT-PCR. IGFBP proteins in conditioned media were detected by Western Ligand Blot. Cell survival after treatment of anti-proliferative agents was assessed by MTT assay. RESULTS: IGF-I and II were expressed in all gastric cancer cell lines. In addition, IGF-I and II stimulated the proliferation of gastric cancer cells. The expression of IGFBP-2 was found in all gastric cancer cell lines. IGFBP-4 was expressed in the most of cell lines. IGFBP-3, -4 and -6 were expressed in about 50% of cell lines. The growth inhibition of IGFBP-3 expressing cells by anti- proliferative agents was more significant than that of IGFBP-3 nonexpressing cells. Cell growth inhibition with treatment of these agents was accompanied by increased IGFBP-3 mRNA level. CONCLUSION: These data confirm that IGF-I, -II, and certain IGFBPs were expressed in gastric cancer cells, and gastric cancer cells show the differential growth inhibition by anti-proliferative agents. The differential growth inhibitory effect of anti-proliferative agents is, at least in part, mediated through up-regulation of IGFBP-3 expression.