sirolimus and Oral-Ulcer

Everolimus (RAD001), a mTOR inhibitor, was initially used as an immunosuppressant in organ transplant patients; however, it also has significant antineoplastic properties. In patients with subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis complex who are not candidates for surgery, single-agent everolimus has demonstrated the ability to significantly reduce SEGA volume with good tolerability. In the Phase III, randomized, placebo-controlled trial, everolimus was associated with a SEGA response rate of 35% compared with 0% in the placebo group. The most common adverse events in clinical trials were stomatitis/mouth ulceration and upper respiratory tract infections, and most adverse events were grade 1 or 2; grade 4 events were rare.

Topics: Animals; Antineoplastic Agents; Astrocytoma; Clinical Trials as Topic; Everolimus; Humans; Oral Ulcer; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Cedecea davisae is a member of the Enterobacteriaceae family and is an uncommon pathogen. This organism has been isolated from the blood, sputum, and cutaneous ulcers of only a handful of patients, most of these being elderly or otherwise medically compromised. This is a report of a patient, status post renal transplantation, who developed an oral ulcer associated with sirolimus use and superinfected with C. davisae. According to the literature, this is the first case of C. davisae detected in the oral cavity. Antibiotic therapy led to prompt resolution of this very large ulcer.

Topics: Adult; Aged; Enterobacteriaceae Infections; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Oral Ulcer; Sirolimus; Superinfection

Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex.. In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828.. 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]).. These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis.. Novartis Pharmaceuticals.

Topics: Adolescent; Adult; Astrocytoma; Child; Child, Preschool; Double-Blind Method; Everolimus; Female; Fever; Humans; Infant; Male; Oral Ulcer; Seizures; Sirolimus; Stomatitis; Treatment Outcome; Tuberous Sclerosis; Young Adult

Oral ulcers is a well-recognised adverse event (AE) of mTOR inhibitors. Paradoxically, little is known about its natural history, risk factors, and basic management.. AEs of 79 patients prospectively enrolled in 6 phase I-II studies testing everolimus were reviewed. The following parameters were analysed: incidence, severity, duration and associated AE. The association between OU and everolimus dose, pharmacokinetics and the effectiveness of empiric treatments were explored.. OU, grade 3-4 OU, prolonged time under OU and RCOU (recurrent and chronic oral ulcer) were observed in 72% 11%, 30% and 25% patients, respectively. Patients with antecedent of prior chemotherapy, with PS 1, or receiving everolimus in combination tended to present higher rates of prolonged time under OU and of grade 3-4 OU. As everolimus daily dose increased, the median time to OU was shorter, the median duration was longer and OU incidence tended to increase. Simultaneously, OU tended to be associated with higher everolimus exposure. None of the empiric treatments appeared effective against OU (preventive or curative intent).. Everolimus-induced OU is a frequent, recurrent and sometimes harmful complication. A dose effect relationship is displayed. Its daily management remains challenging. OU represents a key issue in the compliance of mTOR inhibitors.

Topics: Adult; Aged; Antineoplastic Agents; Dose-Response Relationship, Drug; Everolimus; France; Humans; Male; Middle Aged; Mouthwashes; Oral Ulcer; Prospective Studies; Protein Kinase Inhibitors; Risk Assessment; Risk Factors; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Sirolimus improves post transplant maintenance therapy in LTX. Dermal side effects causing pain and discomfort can limit patients' compliance. The package insert mentions such skin disorders as acne and rash. One case of sirolimus-induced leucocytoclastic vasculitis is reported in the literature.. From July 1998 to October 2003, Sirolimus was implemented in the immunosuppressive protocol in 23 out of 60 liver recipients. Sirolimus target levels are between 3 and <10 ng/dl. Combination with a calcineurinblocker and/or MMF (mycophenolate mofetil) depending on liver function and creatinine is standard. Weekly patient monitoring in the first month after discharge included physical examination, blood samples and immunosuppresant trough levels. Biopsies were taken from untypical efflorescences.. Three patients with non-specific effloresces were reported: one with leucocytoclastic vasculitis and one with exfoliate forearm dermatitis required change of medication while one perivascular lymphocytic eosinophilic dermatitis subsided after dose reduction. In three cases of mouth ulcer, trough levels exceeded 10 ng/dl and in six patients acne diminished after dose reduction. Eighteen out of 23 patients are still receiving sirolimus. Reasons for removal from the study were incompliance and incompatibility. Two patients died.. Immunosuppressants inevitably produce side effects in TX recipients. The positive management of troublesome side effects contributes importantly to compliance and patient survival.

Topics: Acne Vulgaris; Adult; Aged; Dermatitis, Exfoliative; Drug Eruptions; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Oral Ulcer; Sirolimus; Vasculitis, Leukocytoclastic, Cutaneous

In an attempt to reduce calcineurin inhibitor toxicity, transplant patients treated with tacrolimus can be switched to maintenance treatment with sirolimus.. In a prospective, randomized, multicenter trial, 33 kidney transplant recipients on steroid-free maintenance treatment with tacrolimus and mycophenolate mofetil continued tacrolimus and mycophenolate mofetil (control group, n=18) or were converted from tacrolimus to sirolimus (study group, n=15) at 1 year after transplantation.. The study was prematurely stopped as a result of a cluster of nine patients suffering from painful oral ulcerations in the study group. Oral ulcerations did not occur in the control group. The authors here report on the individual cases suffering from this side effect of the instituted immunosuppressive regimen.. The authors review the literature with respect to the occurrence of oral ulcers associated with the use of sirolimus or mycophenolate mofetil and speculate on the causes of the high incidence of oral ulcers in their study group. Possible explanations are overimmunosuppression during the period of the conversion from tacrolimus to sirolimus without antiviral prophylaxis, the use of the oral emulsion instead of tablets, or the lack of corticosteroid co-administration.

Topics: Adult; Aged; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Oral Ulcer; Prospective Studies; Sirolimus

Recently, sirolimus was demonstrated to be effective in treating vascular lesions and lessening the frequency of bleeding and secondary iron deficiency anemia. We present a child with blue rubber bleb nevus syndrome who had prolonged history of iron deficiency anemia secondary to unrecognized gastrointestinal bleeding. Treatment with propranolol, omeprazole and iron had failed. After 2.5 months of sirolimus therapy (trough levels 1 to 5 ng/mL), his hemoglobin concentration improved into the normal range and remained stable. Vascular malformations on both the patient's tongue and in the fundus of his stomach shrank within 5 months of the initiation of sirolimus. In gastrointestinal involvement of blue rubber bleb nevus syndrome sirolimus was found to be effective even in the tongue's vascular lesions.

Topics: Abnormalities, Multiple; Anemia, Iron-Deficiency; Child; Consanguinity; Gastrointestinal Hemorrhage; Gastrointestinal Neoplasms; Heart Septal Defects, Atrial; Humans; Male; Neoplasms, Multiple Primary; Nevus, Blue; Oral Ulcer; Sirolimus; Skin Neoplasms; Tongue Neoplasms

Oral mechanistic target of rapamycin inhibitors have been shown to reduce visceral tumor volume in patients with tuberous sclerosis complex (TSC).. We sought to evaluate the cutaneous response to oral sirolimus in patients with TSC and an indication for systemic treatment, including long-term effects.. A retrospective analysis of 14 adult patients with TSC prescribed sirolimus to treat lymphangioleiomyomatosis was performed. Serial photographs of angiofibromas, shagreen patches, and ungual fibromas taken before, during, and after the treatment period were blinded, then assessed using the Physician Global Assessment of Clinical Condition (PGA). Microscopic and molecular studies were performed on skin tumors harvested before and during treatment.. Sirolimus significantly improved angiofibromas (median treatment duration 12 months; median PGA score 4.5 [range 1.5-5]; Wilcoxon signed rank test, P = .018) and shagreen patches (median treatment duration 10 months; median PGA score 4.5 [range 3.5-5]; Wilcoxon signed rank test, P = .039), whereas ungual fibromas improved in some patients (median treatment duration 6.5 months; median PGA score 4.66 [range 2.75-5]; Wilcoxon signed rank test, P = .109). Clinical, immunohistochemical, or molecular evidence of resistance was not observed (range 5-64 months of treatment).. This was a retrospective analysis limited to adult women with lymphangioleiomyomatosis.. Oral sirolimus is an effective long-term therapy for TSC skin tumors, particularly angiofibromas, in patients for whom systemic treatment is indicated.

Topics: Acne Vulgaris; Administration, Oral; Adult; Antibiotics, Antineoplastic; Drug Administration Schedule; Female; Humans; Middle Aged; Oral Ulcer; Retrospective Studies; Ribosomal Protein S6; Sirolimus; Skin Neoplasms; Treatment Outcome; Tuberous Sclerosis

We report the clinical features and management outcomes in 7 patients with everolimus-related stomatitis.. Fifteen women with hormone-receptor-positive advanced breast cancer receiving everolimus combined with exemestane were prospectively evaluated to assess the development of stomatitis. Oral ulcers were diagnosed based on established criteria.. Seven patients developed stomatitis (46.6%). All patients were treated with topical dexamethasone solution, while everolimus was temporarily discontinued in 4 patients. Stomatitis resolved within 1-2 weeks. Two of the 4 patients, who had interrupted everolimus, developed recurrent stomatitis following drug resume and everolimus was again discontinued and restarted after 2 weeks. To date, 5 patients receive everolimus in full dose. The 2 patients, who developed recurrent stomatitis, received a reduced dose.. Everolimus-related oral ulcers were frequent and led to dose modifications. Controlled trials, endorsing a consensus in terminology, are needed to evaluate measures on prevention and management of this unique toxicity.

Topics: Aged; Androstadienes; Anti-Inflammatory Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Dexamethasone; Everolimus; Female; Follow-Up Studies; Glucocorticoids; Humans; Middle Aged; Oral Ulcer; Prospective Studies; Recurrence; Sirolimus; Stomatitis; Stomatitis, Aphthous; TOR Serine-Threonine Kinases; Treatment Outcome

To evaluate the efficacy and safety of conversion from calcineurin inhibitors to sirolimus among liver transplant recipients with calcineurin inhibitor-induced complications.. After receiving liver transplants, 25 patients with calcineurin inhibitor-induced complications (22 renal dysfunction and 3 new-onset diabetes mellitus) were converted from sirolimus to tacrolimus. The serum creatinine, sirolimus trough level, liver function, acute rejection episodes, and drug-related adverse effects were monitored.. The patients were followed for 12 to 50 months (median, 25 months). The renal function of the 22 patients with renal dysfunction improved after sirolimus conversion. The serum creatinine levels were significantly lower at 3 months after conversion versus before conversion (113.2 ± 21.8 μmol/L vs 163.2 ± 45.3 μmol/L; P < .05). At the end of the follow-up, the average serum creatinine level was 101.9 ± 23.4 μmol/L among the 20 living recipients. Diabetes also was under control in 3 diabetic recipients after the conversion. Four patients experienced episodes of acute rejection, and intravenous steroid bolus therapy was administered in 2 of them. No graft was lost because of acute rejection. The adverse effects of sirolimus included hyperlipidemia (7/25), anemia (8/25), and mouth ulcers (9/25). All these adverse effects were relieved after a short-term symptomatic therapy, and no patient was withdrawn from the conversion trial.. Sirolimus monotherapy is effective and safe in liver transplant recipients. Conversion to sirolimus was associated with a sustained improvement in renal function and diabetes mellitus without an increased incidence of acute rejection episodes.

Topics: Acute Disease; Anemia; Calcineurin Inhibitors; Creatinine; Diabetes Mellitus, Type 2; Follow-Up Studies; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Oral Ulcer; Retrospective Studies; Sirolimus; Tacrolimus

Topics: Adult; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Mycophenolic Acid; Oral Ulcer; Pancreas Transplantation; Sirolimus; Tacrolimus; Tongue Diseases

Topics: Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Oral Ulcer; Sirolimus; Stomatitis, Aphthous; Tongue Diseases

Mouth ulcers are a major complication associated with sirolimus and occasionally result in discontinuation of treatment. However, they continue to be poorly understood and the data in the literature is frequently contradictory. The aim of this retrospective study is to help improve knowledge about such ulcers and about associated risk factors.. The dossiers of 37 renal transplant patients treated with sirolimus between June 2002 and February 2006 were analysed. The data collected consisted of patient age, gender, reason for transplantation, mean dose of sirolimus given and serum concentrations of the drug, ongoing treatments, presence of viral infection, blood picture and serum concentrations of folate, ferritin, iron and vitamin B12, coexistence of chronic inflammatory intestinal disease and local trauma, and presence or absence of mouth ulcers. Clinical investigation of the ulcers was based on notes and photographs taken during visits for oral mucosal disease. Patients presenting ulcers were treated with clobetasol cream and therapeutic efficacy was assessed in terms of progression of pain and speed of healing.. Mouth ulcers were seen in eight of the 37 patients whose dossiers were examined. The sex ratio (M/F) was 1/1 in patients with ulcers and 3/1 in the 29 other patients. In patients presenting ulceration, the doses of sirolimus administered and serum sirolimus concentrations were respectively 3.2+/-1.05mg and 9.5+/-3.6ng/l versus 3.2+/-1.7mg and 9.8+/-4.1ng/l in patients without ulcers. The diseases responsible for renal failure were comparable in the two groups. 62% of patients with mouth ulcers discontinued sirolimus versus 65% of those without mouth ulcers. Only one patient stopped taking sirolimus partly on account of mouth ulcers. Mycophenolate mofetil was combined with sirolimus in 62.5% of patients with ulceration and in 62% of patients with no ulceration. The forms of ulceration varied, with a fibrinoid base. The edges were not excessively raised and no peripheral erythematous border was observed. Size ranged from 1 to 15mm, with between two and five ulcers being seen. The covering mucosa was involved in all cases, with sparing of the masticatory and specialised mucosa. Histological examination revealed non-specific ulceration associated with a polymorphous inflammatory infiltrate. Treatment with clobetasol reduced pain and shortened healing times between two- and three-fold.. This study confirmed the incidence of mouth ulcers in renal transplant patients treated with sirolimus. The ulcers did not appear to be attributable to a dose-dependent mechanism, thus corroborating the results reported in the literature. However, a contributory role of transition from tacrolimus to sirolimus in their appearance was not seen in this study. Combination of sirolimus with mycophenolate mofetil appeared to have no bearing on the incidence of mouth ulcers. Clobetasol cream, whether or not given together with an anaesthetic solution, appears to reduce pain and shorten healing times, and could thus avoid discontinuation of treatment on account of mouth ulcers.

Topics: Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mouth Mucosa; Oral Ulcer; Retrospective Studies; Sirolimus

Posttransplant lymphoproliferative disorders are a group of lymphoid proliferations and lymphomas that develop as a consequence of immunosuppression in recipients of solid organ or bone marrow allografts. We describe an unusual oral presentation of posttransplant Epstein-Barr virus-associated diffuse large B-cell lymphoma in a 45-year-old woman after pancreatic transplant.

Topics: Diagnosis, Differential; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Mouth Neoplasms; Oral Ulcer; Pancreas Transplantation; RNA, Viral; Sirolimus; Tongue Diseases

Transgene-encoded therapeutic secretory proteins can be efficiently secreted from salivary glands into saliva or the bloodstream after adenoviral (Ad)-mediated gene transfer. Since transgene expression from conventional vectors is typically unregulated, we evaluated the rapamycin-based dimerizer regulation system for control of transgene expression in, and consequent exocrine protein secreted from, rat salivary glands. We used human growth hormone (hGH) as a surrogate exocrine secretory protein. Two Ad vectors, Ad C4ZF3, encoding activation and DNA binding domain fusion polypeptides, and Ad Z12-I-GH-2, encoding hGH, were constructed and shown useful in vitro. Thereafter, both vectors were delivered into submandibular glands by retroductal infusion. After 24 h, rapamycin (0, 1, 3 or 10 mg/kg) was administered, and 20 h later hGH levels in saliva were determined. Salivary hGH levels were rapamycin concentration dependent. At a rapamycin dose of 10 mg/kg, total salivary hGH was 693+/-197 ng and the hGH concentration in saliva was 4.6+/-1.3 microg/ml. Over a 16-day experimental period, three separate administrations of rapamycin (3 mg/kg) induced distinct elevations of salivary hGH (approximately 100-200 ng total hGH) that were entirely rapamycin dependent. This study demonstrates for the first time pharmacological control of transgenic exocrine protein production and presence in saliva after salivary gland gene transfer, and the potential for its application to the management of oral, oropharyngeal and upper gastrointestinal tract disorders.

Topics: Adenoviridae; Animals; Anti-Bacterial Agents; Cell Line; Gene Expression; Genetic Therapy; Genetic Vectors; Human Growth Hormone; Humans; Oral Ulcer; Pilocarpine; Rats; Saliva; Sirolimus; Transduction, Genetic; Transgenes

Calcineurin inhibitors have dramatically improved the outcomes of pediatric liver transplantation. However, calcineurin inhibitor use is associated with a 50% reduction in glomerular filtration rate in the first year post-transplant. Nephrotoxicity can be difficult to manage, especially in the pediatric population. We hypothesized that the addition of an mTOR inhibitor with decreased calcineurin inhibitor levels might improve or prevent renal insufficiency and improve control of rejection. A retrospective chart review was performed on the patients treated with sirolimus who had undergone an orthotopic liver transplant between January 2000 and February 2003. Thirty-eight patients were identified. Mean age was 8.6 yr. Fourteen patients were male and 24 were female. Mean weight was 30.3 kg. The most common indications for starting sirolimus were rejection (42%) and renal impairment (29%). Seventy-three percent of patients begun on sirolimus remain on the medication. Those with renal impairment (11 patients) showed improvement in their creatinine levels from a mean baseline of 1.3 to 0.8 mg/dL. Their calculated creatinine clearance (Schwartz formula) improved from 63.7 to 84.8 mL/min (p = 0.03). Patients started on sirolimus for rejection showed significant improvement in hepatocellular enzymes despite a reduction in the tacrolimus level from 12.2 to 7.5 ng/mL. The mean alanine aminotransferase level improved from 221 to 100 units/L (p = 0.02), and the mean aspartate aminotransferase improved from 121 to 99 units/L (p = 0.59). Addition of sirolimus to a tacrolimus-based regimen with lower target tacrolimus levels improved liver function in patients with rejection. Addition of sirolimus significantly improved renal function as shown by creatinine level and calculated creatinine clearance in those children with renal impairment. The effect of combined immunosuppressant treatment with tacrolimus and sirolimus on long-term renal function needs to be evaluated.

Topics: Adolescent; Adult; Child; Child, Preschool; Creatinine; Drug Therapy, Combination; Female; Hepatitis; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Neutropenia; Oral Ulcer; Postoperative Care; Retrospective Studies; Sirolimus; Tacrolimus; Treatment Outcome

Sirolimus (SRL) is a powerful immunosuppressant used primarily in calcineurin inhibitors (CNI)-related nephrotoxicity. However, reports of drug-related side effects are increasing. The aim of our report is to review the frequency and timing of these complications within our transplant patient population.. We retrospectively reviewed the medical records of liver-transplanted patients treated with sirolimus between November 1998 and April 2002. The data collected included SRL serum levels, frequency of reported and documented SRL-related side effects, and survival outcomes. Statistical evaluation included Pearson chi-square and the Fisher's exact tests.. Overall, 205 patients were identified, with 30 patients removed from the analysis for different reasons. Of the remaining 175 patients, 91 (52%) patients developed a complication other than an increase in serum triglycerides and/or cholesterol. The most frequent complications were: bilateral lower extremity edema (57.1%), dermatitis (25.3%), oral ulcers (24.2%), joint pain (23.0%), pleural effusion (16.5%) and increase in abdominal girth (9.9%). Other complications included: generalized edema (5.5%), pericardial effusion (5.5%), facial edema (2.2%), and upper extremity edema (1.3%). In addition, we reported two cases of hepatic artery thrombosis, one case of wound dehiscence with evisceration that required surgical repair, and one case of skin cancer. Interestingly, we found that a previous history of myocardial ischemia correlates with the development of SRL side effects.. SRL is a powerful immunosuppressant but not devoid of side effects. These results have elevated our level of suspicion when instituting SRL and may help with early recognition and prevention of drug related complications.

Topics: Edema; Humans; Immunosuppressive Agents; Liver Transplantation; Oral Ulcer; Patient Selection; Postoperative Complications; Retrospective Studies; Sirolimus