sirolimus and Drug-Hypersensitivity

Topics: Angioplasty, Balloon, Coronary; Atherosclerosis; Coronary Restenosis; Drug Hypersensitivity; Drug-Eluting Stents; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Paclitaxel; Shear Strength; Sirolimus

Mammalian target of rapamycin (mTOR) has emerged as an important target for cancer therapy. Rapamycin has a distinct, well-documented toxicity profile and most of the toxicity data has been reported in patients with organ transplantation. Newer mTOR inhibitors have slightly different pharmacokinetic properties, yet they present toxicity profiles similar to rapamycin. Most of these toxicities are mild to moderate in severity and can be managed clinically by dose modification and supportive measures. Mucositis and pneumonitis are the most commonly reported toxicities, but they rarely lead to treatment discontinuation. Pathogenesis of pneumonitis is uncertain, but various hypotheses have been suggested, including cell-mediated immune response to the drug.

Topics: Animals; Antineoplastic Agents; Drug Hypersensitivity; Graft Rejection; Humans; Mucositis; Neoplasms; Organ Transplantation; Pneumonia; Prognosis; Protein Kinases; Sirolimus; Th1 Cells; Th2 Cells; TOR Serine-Threonine Kinases; Treatment Outcome

Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC.. Patients were enrolled onto a multicenter, ascending-dose study of temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information.. Seventy-one patients were entered to receive one of six dose levels. The recommended dose was temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia for all patients and those who received the recommended dose. Among patients who received the recommended dose (n = 39), 8% achieved partial response and 36% had stable disease for at least 24 weeks. Median progression-free survival for all patients in the study was 9.1 months.. The combination of temsirolimus and IFN has an acceptable safety profile and displays antitumor activity in patients with advanced RCC. Temsirolimus 15 mg plus IFN 6 MU is the recommended dose for evaluation in a randomized phase III study.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carcinoma, Renal Cell; Digestive System Diseases; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Hypersensitivity; Exanthema; Female; Humans; Interferon-alpha; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Respiratory Tract Diseases; Sirolimus

Topics: Drug Hypersensitivity; Drug-Eluting Stents; Humans; Male; Middle Aged; Sirolimus; Tomography, Optical Coherence; United States; United States Food and Drug Administration

Topics: Alveolitis, Extrinsic Allergic; Biopsy; Drug Hypersensitivity; Drug-Eluting Stents; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Sirolimus; Steroids; Tomography, X-Ray Computed; Treatment Outcome

While drug eluting stents (DES) are being more widely used in ever more patients receiving DES each day, some new complications may be emerging. Stent fractures and hypersensitivity reactions to stents are among recognized complications that can lead to therapeutic dead end from the interventional cardiologist's point of view. We present a case in which we reached therapeutic dead end with a sirolimus eluting stent, i.e. repetitive stent fractures with diffuse microaneurysms along the implanted DES, possibly due to hypersensitivity reaction to parts of the stent.

Topics: Coronary Aneurysm; Coronary Angiography; Coronary Restenosis; Drug Hypersensitivity; Drug-Eluting Stents; Equipment Failure; Female; Humans; Hypersensitivity, Delayed; Middle Aged; Sirolimus

Sirolimus (rapamycin) is an immunosuppressant used in preventing allograft rejection and in drug-eluting stents to prevent restenosis after angioplasty. Zotarolimus, an analogue of sirolimus, was designed to have a shorter in vivo half-life. Zotarolimus was found to be mechanistically similar to sirolimus in having high-affinity binding to the immunophilin FKBP12 and comparable potency for inhibiting in vitro proliferation of both human and rat T cells. Rat pharmacokinetic studies with intravenous dosing demonstrated terminal elimination half-lives of 9.4 hours and 14.0 hours for zotarolimus and sirolimus, respectively. Given orally, T1/2 values were 7.9 hours and 33.4 hours, respectively. Consistent with its shorter duration, zotarolimus showed a corresponding and statistically significant 4-fold reduction in potency for systemic immunosuppression in 3 rat disease models. Pharmacokinetic studies in cynomolgus monkey underpredicted the half-life difference between zotarolimus and sirolimus apparent from recent clinical data. In vitro inhibition of human coronary artery smooth muscle cell proliferation by zotarolimus was comparable to sirolimus. Drug-eluting stents for local delivery of zotarolimus to the vessel wall of coronary arteries are in clinical development. The pharmacological profile of zotarolimus suggests it may be advantageous for preventing restenosis with a reduced potential for causing systemic immunosuppression or other side effects.

Topics: Animals; Animals, Newborn; Binding, Competitive; Cell Proliferation; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Hypersensitivity; Encephalomyelitis, Autoimmune, Experimental; Graft Rejection; Half-Life; Heart Transplantation; Humans; Hypersensitivity, Delayed; Immunosuppressive Agents; Inhibitory Concentration 50; Lymphocyte Culture Test, Mixed; Male; Myocytes, Smooth Muscle; Rats; Rats, Inbred BN; Rats, Inbred Lew; Rats, Sprague-Dawley; Sirolimus; T-Lymphocytes; Tacrolimus Binding Protein 1A

We undertook the review of all available cases of hypersensitivity reactions after placement of a drug-eluting stent (DES) and classified potential causes.. Six months after the approval of the first DES, the Food and Drug Administration (FDA) reported 50 hypersensitivity reactions after stent placement but later concluded these were due to concomitantly prescribed medications such as clopidogrel. Nevertheless, the FDA continued to receive reports of hypersensitivity.. Reports available from April 2003 through December 2004 for hypersensitivity-like reactions associated with the sirolimus-eluting stent (CYPHER, Cordis Corp., Miami Lakes, Florida) and paclitaxel-eluting stent (TAXUS, Boston Scientific Corp., Natick, Massachusetts) were reviewed. Sources of reports included the FDA's adverse-device-event database, the published literature, and investigators from the Research on Adverse Drug/Device events And Reports (RADAR) project. Causality was assessed using standardized World Health Organization criteria.. Of 5,783 reports identified for the DES in the FDA database, 262 unique events included hypersensitivity symptoms. Of these reports, 2 were certainly and 39 unlikely caused by clopidogrel and 1 was certainly, 9 probably, and 13 unlikely caused by the DES. From all sources, we identified 17 distinct cases that were probably or certainly caused by the stent, of which 9 had symptoms that lasted longer than four weeks. Four autopsies confirmed intrastent eosinophilic inflammation, thrombosis, and lack of intimal healing.. The FDA reports and autopsy findings suggest that DES may be a cause of systemic and intrastent hypersensitivity reactions that, in some cases, have been associated with late thrombosis and death.

Topics: Coronary Vessels; Drug Hypersensitivity; Humans; Paclitaxel; Sirolimus; Stents

Topics: Coronary Vessels; Drug Hypersensitivity; Humans; Hypersensitivity; Paclitaxel; Sirolimus; Stents

Topics: Aged; Angioplasty, Balloon, Coronary; Citrates; Coronary Stenosis; Coronary Vessels; Drug Hypersensitivity; Drug Implants; Eosinophilia; Female; Gallium; Gallium Radioisotopes; Humans; Pericardial Effusion; Radionuclide Imaging; Radiopharmaceuticals; Sirolimus; Stents; T-Lymphocytes

Topics: Angioplasty, Balloon, Coronary; Coronary Aneurysm; Coronary Angiography; Coronary Stenosis; Drug Hypersensitivity; Drug Implants; Equipment Failure; Female; Humans; Middle Aged; Sirolimus; Stents

Topics: Animals; Coronary Thrombosis; Drug Hypersensitivity; Drug Implants; Humans; Male; Middle Aged; Mycophenolic Acid; Rats; Sirolimus; Stents

Drug-eluting stents have reduced the frequency of in-stent restenosis. However, most of the results have been derived from simple lesions in noncomplex patients. In preclinical normal pig and rabbit studies, bare-metal stents show complete healing at 28 days, whereas drug-eluting stents show incomplete healing with persistence of fibrin and incomplete coverage of the stent struts by endothelial cells. In human beings similar delayed healing has been observed at 6 and 12 months in atherectomy specimens or at autopsy. The US Food and Drug Administration posted adverse event information for physicians regarding subacute thrombosis and hypersensitivity reaction following deployment of sirolimus-eluting stents in human beings. The authors have seen, at autopsy, late (18 months) stent thrombosis, aneurysm formation, and extensive inflammatory reaction limited to the arterial wall surrounding the stent that they interpret as a hypersensitivity reaction to the polymer. The authors advocate caution and aggressive use of nontoxic systemic drugs to prevent the complications of atherosclerosis along with better postmarket surveillance of patients and histologic examination of tissue from patients with drug-eluting stents.

Topics: Aneurysm; Angioplasty, Balloon, Coronary; Animals; Autopsy; Coronary Artery Disease; Coronary Restenosis; Disease Models, Animal; Drug Delivery Systems; Drug Hypersensitivity; Follow-Up Studies; Granuloma, Foreign-Body; Humans; Immunosuppressive Agents; Male; Middle Aged; Polymers; Rabbits; Randomized Controlled Trials as Topic; Safety; Sirolimus; Stents; Swine; Thrombosis; Time Factors

Rapamycin prolongs allograft survival and induces donor-specific tolerance in some small animal transplant models. Large animal studies, however, are limited. We studied rapamycin in a porcine renal allograft model. Donor-recipient combinations were chosen based on high response in pretransplant MLCs. Allografts were anastomosed to the aorta and vena cava and the native kidneys removed. There were 5 treatment groups: (a) no immunosuppression; (b) triple therapy (CsA, 1 mg/kg/day; AZA, 2-3 mg/kg/day; and PRED, 3-4 mg/kg/day); (c) rapamycin (0.75 mg/kg/day i.m.) in carboxymethylcellulose (CMC); (d) rapamycin (0.25 mg/kg/day i.m. in CMC); and (e) a vehicle (CMC) control. Serum creatinine levels were determined every other day. Most allografts were biopsied once a week. Immunosuppression was stopped after 30 days. Mean graft survival in nonimmunosuppressed recipients was 6.8 +/- 3.6 days. Mean graft survival in triple therapy recipients (n = 10) was 45.7 +/- 36 days vs. 59.6 +/- 11.4 days in rapamycin (0.25 mg/kg/day) recipients (n = 7) (P = 0.51). Both triple therapy and rapamycin improved renal allograft survival versus nonimmunosuppressed controls (P = 0.0025 and 0.001, respectively). Serum creatinine levels were significantly lower (P < 0.05) in rapamycin versus triple therapy recipients. We conclude that rapamycin is a potent immunosuppressant in a porcine renal allograft model and may avoid the elevated serum creatinine levels associated with CsA.

Topics: Animals; Drug Administration Schedule; Drug Hypersensitivity; Graft Survival; Immunosuppressive Agents; Kidney Transplantation; Male; Models, Biological; Polyenes; Sirolimus; Swine; Transplantation, Homologous