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At least 19 recordsLinked to original sources
PubMed2026

Comparative effectiveness of percutaneous coronary intervention strategies for coronary small-vessel disease: a network meta-analysis of randomized trials.

BACKGROUND: Coronary small-vessel disease (SVD) remains challenging for percutaneous coronary intervention (PCI) because small lumens magnify restenosis and ischemic risk. Multiple devices are available, yet their comparative performance is uncertain. This study evaluated and ranked PCI strategies for SVD. METHODS: A systematic review and network meta-analysis was conducted in accordance with PRISMA. PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and Google Scholar were searched from inception to 15 August 2025. Eligible studies were English-language randomized controlled trials enrolling adults with angiographic SVD defined as reference vessel diameter ≤3.0 mm, comparing PCI strategies, and reporting target lesion revascularization (TLR), binary restenosis (BR), or myocardial infarction (MI). A frequentist random-effects network meta-analysis generated odds ratios (ORs) with 95% confidence intervals (CIs) and treatment rankings using the surface under the cumulative ranking curve (SUCRA). RESULTS: Thirty-nine trials including 14,503 patients met the criteria. For TLR (37 studies; 11,980 patients), the highest SUCRA values were observed with sirolimus-eluting stents (SES 90.1%), zotarolimus-eluting stents (ZES 83.9%), and everolimus-eluting stents (EES 82.2%). For BR (32; 6,468), SES, ZES, and paclitaxel-coated balloons (DCB-PTX) ranked highest (95.0%, 80.0%, and 78.3%). For MI (37; 11,602), SES, DCB-PTX, and ZES ranked highest (79.0%, 78.7%, and 68.5%). Representative effects showed SES reduced TLR versus bare-metal stents (BMS) (OR, 0.25; 95% CI, 0.15-0.43) and MI versus BMS (OR, 0.41; 95% CI, 0.21-0.79). Conventional approaches such as BMS, plain old balloon angioplasty (POBA), and gold-plated balloon angioplasty (GPBA) ranked lowest across outcomes. CONCLUSION: SES provides the most consistent clinical benefit for coronary SVD. ZES, EES, and DCB-PTX are effective alternatives in selected settings, whereas BMS, POBA, and GPBA are less effective. These findings offer comparative evidence to guide device selection in SVD.

Humans↗
PubMed2024

Drug repurposing in status epilepticus.

The treatment of status epilepticus (SE) has changed little in the last 20 years, largely because of the high risks and costs of new drug development for SE. Moreover, SE poses specific challenges to drug development, such as patient diversity, logistical hurdles, and the need for acute treatment strategies that differ from chronic seizure prevention. This has reduced the appetite of industry to develop new drugs in this area. Drug repurposing is an attractive approach to address this unmet need. It offers significant advantages, including reduced development time, lower costs, and higher success rates, compared to novel drug development. Here I demonstrate how novel methods integrating biological knowledge and computational methods can be applied to drug repurposing in status epilepticus. Biological approaches focus on addressing mechanisms underlying drug resistance in SE (using for example ketamine, tacrolimus and safinamide) and longer-term consequences (using for example omaveloxolone, celecoxib and losartan). Additionally, artificial intelligence platforms, such as ChatGPT, can rapidly generate promising drug lists, while in silico methods can analyze gene expression changes to predict molecular targets. Combining AI and in silico approaches has identified several candidate drugs, including metformin, sirolimus and riluzole, for SE treatment. Despite the promise of repurposing, challenges remain, such as intellectual property issues and regulatory barriers. Nonetheless, drug repurposing presents a viable solution to the high costs and slow progress of traditional drug development for SE. This paper is based on a presentation made at the 9th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures, in April 2024.

Animals↗
PubMed1990

Suppression of B cell activation by cyclosporin A, FK506 and rapamycin.

The effects of the immunosuppressants cyclosporin A (CsA), FK506 and rapamycin have been compared using murine B cells activated with a variety of mitogens. FK506 is a macrolide antibiotic that has been recently shown to inhibit T cell activation by a mechanism that appears similar to that of CsA. Rapamycin is a macrolide structurally related to FK506 whose mechanism of T cell suppression appears to be distinct from that of FK506 and CsA. While CsA and FK506 were found to preferentially inhibit B cell activation caused by stimuli which induce a rise in intracellular calcium, rapamycin partially inhibited activation by all stimuli tested, including those which are not associated with a calcium flux. All three compounds were found to inhibit cell cycle progression within the G1 phase; however, the rapamycin-sensitive event within G1 was completed earlier than the G1 events inhibited by CsA and FK506. In addition, inhibition of anti-IgM-activated B cells with CsA and FK506, but not with rapamycin, resulted in cell death. These data suggest that although CsA, FK506 and rapamycin are all inhibitors of B cell activation, the inhibitory activity of rapamycin can be clearly distinguished from that of CsA and FK506. Although the suppressive effects of CsA and FK506 on B cell proliferation were nearly identical in this study, their biological activities were distinguishable since FK506, but not CsA, could antagonize rapamycin-mediated suppression.

Animals↗
PubMed1991

The effect of the immunosuppressant FK-506 on alternate pathways of T cell activation.

Structurally unrelated, FK-506 and cyclosporin (CsA) bind to and inhibit the action of distinct cytoplasmic receptors, FK-506-binding protein (FKBP) and cyclophilin (CyP), respectively. These receptors, termed immunophilins, share no sequence similarity, and yet both have been demonstrated to be capable of catalyzing the cis-trans isomerization of peptidyl-prolyl bonds (rotamase activity). Because FK-506 and CsA bind to different intracellular target structures, we investigated the spectrum of action of FK-506, in comparison to CsA, on T cell activation. We have shown that FK-506, like CsA, is able to inhibit T cell activation mediated not only by the T cell receptor-CD3 complex, but also via another surface molecule, CD2. T cell proliferation, stimulation of interleukin 2 production, and induction of apoptosis were all sensitive to inhibition by both FK-506 and CsA. With each parameter of activation, FK-506 is approximately 10-100-fold more effective than CsA. In contrast, FK-506 did not affect T cell proliferation induced by anti-CD28 monoclonal antibody in the presence of phorbol 12-myristate 13-acetate. This CD28 pathway, however, was inhibited by a structural homology of FK-506, rapamycin, demonstrating that the mechanism of action of FK-506 has specificity. These data suggest that immunophilins or the complex of drug coupled to immunophilin (i.e. FK-506/FKBP, CsA/CyP) are involved in and regulate selective pathways of T cell stimulation.

Animals↗
PubMed1992

Correlation of calcineurin phosphatase activity and programmed cell death in murine T cell hybridomas.

Ligation of T cell receptor/CD3 complexes induces programmed cell death, or apoptosis, in immature thymocytes and many T cell hybridomas. While it has been demonstrated that T cell receptor-mediated apoptosis requires an increase in intracellular calcium concentration, the specific calcium-dependent signalling events leading to cell death are poorly defined. We have previously shown that T cell receptor/CD3-mediated induction of apoptosis in a murine T cell hybridoma is inhibited by the immunosuppressive drugs cyclosporin A (CsA) and FK506. Recently, it has been determined that these agents inhibit the activity of calcineurin, a calcium- and calmodulin-dependent serine/threonine phosphatase. Using an assay which measures calcineurin activity in cell lysates, we find that calcineurin-dependent dephosphorylation of a phosphopeptide substrate is potently inhibited in hybridomas treated with CsA or FK506. Drug dose-response analyses indicate that the level of cellular calcineurin activity correlates closely with the ability of these cells to undergo apoptosis. Thus, calcineurin appears to be a critical mediator of T cell receptor/CD3 signalling leading to programmed cell death in T cell hybridomas.

Amino Acid Sequence↗
PubMed1992

Effects of rapamycin on cultured hepatocyte proliferation and gene expression.

Rapamycin, a potent immunosuppressive drug that disrupts normal signal-transduction processes, inhibited hepatocyte proliferation without evidence of inherent cytotoxicity in rat hepatocytes cultured in conventional medium or in a medium enriched with epidermal growth factor. The antiproliferative effect was dose dependent, uninfluenced by the concentration of epidermal growth factor in the medium and long lasting after a brief exposure. The effect of rapamycin was unaltered by the concomitant presence of FK 506 in the medium, suggesting that different binding affinities of these two drugs or even a separate rapamycin binding site may exist. Hepatocytes harvested 12 and 24 hr after partial hepatectomy were progressively less responsive to the antiproliferative effect of rapamycin. The gene expression of transforming growth factor-beta was reduced under in vivo rapamycin treatment, but at the same time the gene expression of albumin and glyceraldehyde-3-phosphate dehydrogenase was unchanged or increased. The experiments confirm that rapamycin has inherent growth-control qualities, and they strengthen the hypothesis that the recently defined immunophilin network is central to many aspects of cellular growth control.

Animals↗
PubMed1991

Complete amino acid sequence of the FK506 and rapamycin binding protein, FKBP, isolated from calf thymus.

FKBP, an 11.8 kD intracellular protein that binds the immunosuppressants FK506 (Kd = 0.4 nM) and rapamycin (Kd = 0.2 nM) with high affinity, was purified to homogeneity from calf thymus. The complete amino acid sequence has been determined by automated Edman degradation of the intact molecule and overlapping fragments generated by proteolytic and chemical cleavage. The analysis revealed a 107 amino acid peptide chain with the following sequence: GVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFV- LGKQEVIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPNATLIFDVELLKLE. The molecular weight, calculated from the amino acid sequence to be 11,778 D, was confirmed by electrospray ionization mass spectrometry. Thus, naturally isolated bovine FKBP does not appear to have any residues modified by glycosylation, phosphorylation, or other posttranslational derivatization processes. Bovine FKBP has only three amino acid residues that differ from human FKBP, whose sequence was elucidated by cloning and sequencing complementary DNA (Standaert et al., 1990). The protein has a substantial number of hydrophilic peptide segments with prevalent beta-strand type of chain fold. Understanding the biological function of FKBP and other members of the immunophilin class and their respective complexes with immunosuppressive drugs may provide insights into cytoplasmic signalling mechanisms, protein folding and translocation, and other cellular processes.

Amino Acid Sequence↗
PubMed1991

Corticosteroids and immunosuppressive agents in rabbit heterolamellar corneal transplant model.

Bovine cornea (epithelium and stroma) was transplanted on to the rabbit cornea from which the epithelium and stroma had been removed. Conjuntival hyperemia and edema occurred from day 1-5 post-operation, followed by neovascularization and graft rejection within 7-10 days. Topical dexamethasone (0.1%) and prenisolone (1%) t.i.d. inhibited post-surgical hyperemia, edema, delayed hypersensitivity and neovascularization. These agents and the immunosuppressants (cyclosporin A and rapamycin) inhibited graft rejection observed up to 20 days. After cessation of treatment on the 20th day, grafts remained viable up to 35 days with dexamethasone, 10 days with prednisolone and rapamycin, and 5 days with cyclosporin A.

Adrenal Cortex Hormones↗
PubMed1992

New immunosuppressive drugs: needs in and applications to pediatric transplantation.

The evolution of immunosuppressive therapy toward synergistic drug combinations seeks to minimize toxicity while potentiating efficacy. Median effect analysis discerns synergistic drug combinations that may be suitable for in vivo experiments in animals and for subsequent clinical trials. These studies suggest that two drugs rapamycin (RAPA) and brequinar (BQR) display synergistic effects in combination with cyclosporine. This combination must be evaluated for relative toxicity versus efficacy. Clinical trials to assess the individual toxicities of RAPA and BQR are presently underway in order to discern appropriate doses for randomized trials of clinical efficacy.

Child↗
PubMed1992

cDNA cloning of a human 25 kDa FK506 and rapamycin binding protein.

The abilities of FK506 and rapamycin to block distinct signal transduction pathways are mediated by soluble binding proteins. Previously, a family of these receptors has been recognized that includes a 25 kDa protein, FKBP25. We now report the isolation of a cDNA for FKBP25 from a human hippocampal cDNA library by oligonucleotide screening. The nucleotide sequence reveals an open reading frame that encodes a 224 amino acid polypeptide. Human FKBP25 shows 97% amino acid identity with bovine FKBP25 and 62% homology with human FKBP12.

Amino Acid Sequence↗
PubMed1992

Leukocyte chemotactic activity of FKBP and inhibition by FK506.

Cyclophilin, the cyclosporin A binding protein and member of the immunophilin family of proteins, demonstrates leukocyte chemotactic activity. In this study we demonstrate that FKBP, the FK506 and rapamycin binding protein, also displays leukocyte chemotactic activity. The chemotactic activity of FKBP is inhibited by FK506, however, FK506 was unable to inhibit cyclophilin-stimulated chemotactic activity. Rapamycin was unable to prevent the chemotactic activity of FKBP, similarly, the CsA analogue Me6Ala-CsA while displaying cyclophilin binding was unable to block cyclophilin-stimulated chemotactic activity. These results suggest that in addition to their intracellular role the immunophilins may also function as chemotactic agents, furthermore this activity is modulated by immunosuppressants.

Amino Acid Isomerases↗
PubMed1991

FK-506 and cyclosporin A: selective inhibition of calcium ionophore-induced polymorphonuclear leukocyte degranulation.

This paper investigates the abilities of FK-506 and cyclosporin A (CsA) to inhibit human polymorphonuclear leukocyte (PMNL) degranulation. PMNLs, purified from human blood, were stimulated in vitro with A23187, ionomycin, the complement derived peptide C5a, formylmethionylleucinylphenylalanine (FMLP) or phorbol myristate acetate (PMA). Degranulation was assessed by measuring the release of either lactoferrin or N-acetyl-beta-D-glucosaminidase (NAG). Both FK-506 and CsA produced a concentration-related inhibition of degranulation induced by either A23187 or ionomycin but did not affect C5a-, FMLP- or PMA-induced degranulation. The IC50 values for inhibition of degranulation (approximately 0.7 nM for FK-506 and 33.7 nM for CsA) are very close to the published values for inhibition of human T-cell proliferation. Removal of calcium from the incubation medium with ethyleneglycolbis(aminoethylether)tetra-acetate (EGTA) totally inhibited calcium ionophore-induced degranulation but had no effect against C5a-, FMLP- or PMA-induced degranulation. Preincubation of PMNLs with actinomycin D or cycloheximide did not affect either A23187- or PMA-induced degranulation. Non-immunosuppressive analogs of CsA were ineffective at inhibiting degranulation. Rapamycin, a macrolide structurally related to FK-506, did not inhibit degranulation but it did antagonize the inhibition produced by FK-506. Given the similar profiles of activity of FK-506 and CsA in neutrophils and T cells, we conclude that similar activation or signal transduction pathways may be present in both T cells and neutrophils. Because A23187-induced PMNL degranulation was not sensitive to either actinomycin D or cycloheximide, it is apparent that the signal transduction pathways ultimately control different cellular functions.

Anti-Bacterial Agents↗
PubMed1992

A modification of the in vivo mixed lymphocyte reaction and rapamycin's effect in this model.

Rapamycin, a novel macrocyclic immunosuppressive agent, suppresses murine T cell activation in vitro by mechanisms distinct from cyclosporin A (CsA). This study was designed to examine rapamycin and CsA in the host vs graft popliteal lymph node (PLN) model, an in vivo system of T cell-dependent lymphocyte activation. The PLN procedure was modified by using irradiated CTLL-2 cells of C57BL/6 origin, instead of primary mouse splenocytes, as the allogeneic stimulus in C3H/HeN recipient mice. PLN cell proliferation was determined by [3H]-thymidine uptake. We found that the host lymphocyte proliferative response to CTLL-2 cells (H-2b) is greater than the response to mouse Balb/c splenocytes (H-2d). Rapamycin (ip or po) produced a dose-related inhibition of the in vivo mixed lymphocyte reaction. By contrast, the effects of CsA and FK-506 were not dose related within the same dose range (0.006-12 mg/kg). These data indicate that rapamycin is an effective immunosuppressive agent and confirm its ability to affect the allogeneic T cell response in vivo. Furthermore, the pharmacological data suggest that this PLN model utilizing irradiated CTLL-2 cells as an allogeneic stimulus provides a reproducible system to examine mixed lymphocyte reactions in vivo.

Animals↗
PubMed1992

Effects of rapamycin on human HLA-unrestricted cell killing.

Rapamycin (RAPA) is a potent immunosuppressant and can effectively prevent allograft rejection at a dosage 10- to 100-fold lower than that of cyclosporin A. RAPA strongly inhibits proliferation and function of T and B cells. In this study, we investigated the effect of RAPA on human HLA-unrestricted cell killing. It was shown that in vitro RAPA inhibited the cytolytic effect of natural killer cells and lymphokine-activated killer cells (LAK) and inhibited antibody-dependent cell-mediated cytotoxicity. The effective concentration of RAPA was 10- to 100-fold higher than that required for inhibiting T cell proliferation. These results suggest that there could be a therapeutic dose window at which RAPA inhibits T cell activity while it leaves HLA-unrestricted cell killing unaffected. We also demonstrated that while IL4 inhibited LAK activity, and RAPA inhibited IL4-promoted T cell proliferation, RAPA was not able to antagonize IL4's inhibitory effect on LAK. This indicates that the mechanism of interaction between RAPA and IL4 on LAK is different from that on T cells.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1991

Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.

Although the immediate receptors (immunophilins) of the immunosuppressants cyclosporin A (CsA) and FK506 are distinct, their similar mechanisms of inhibition of cell signaling suggest that their associated immunophilin complexes interact with a common target. We report here that the complexes cyclophilin-CsA and FKBP-FK506 (but not cyclophilin, FKBP, FKBP-rapamycin, or FKBP-506BD) competitively bind to and inhibit the Ca(2+)- and calmodulin-dependent phosphatase calcineurin, although the binding and inhibition of calcineurin do not require calmodulin. These results suggest that calcineurin is involved in a common step associated with T cell receptor and IgE receptor signaling pathways and that cyclophilin and FKBP mediate the actions of CsA and FK506, respectively, by forming drug-dependent complexes with and altering the activity of calcineurin-calmodulin.

Amino Acid Isomerases↗