Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects.

BACKGROUND: The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established. METHODS: We enrolled in our study 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both to assess the cardiovascular consequences of weight management with and without sibutramine in subjects at high risk for cardiovascular events. All the subjects received sibutramine in addition to participating in a weight-management program during a 6-week, single-blind, lead-in period, after which 9804 subjects underwent random assignment in a double-blind fashion to sibutramine (4906 subjects) or placebo (4898 subjects). The primary end point was the time from randomization to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death). RESULTS: The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P=0.03). The rates of cardiovascular death and death from any cause were not increased. CONCLUSIONS: Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.)

Successful reinstitution of agalsidase beta therapy in Fabry disease patients with previous IgE-antibody or skin-test reactivity to the recombinant enzyme.

PURPOSE: To determine if enzyme replacement therapy, involving intravenous infusions of recombinant human alpha-galactosidase A (agalsidase beta; Fabrazyme), could be safely continued in patients with Fabry disease who had been withdrawn from a previous clinical trial as a precautionary, protocol-specified measure due to detection of serum IgE antibodies or skin-test reactivity to agalsidase beta. METHODS: The rechallenge infusion protocol specified strict patient monitoring conditions and graded dosing and infusion-rate schemes that were adjusted according to each patient's tolerance to the infusion. Six males (age: 26-66 years) were enrolled. RESULTS: During rechallenge, five patients received between 4 and 27 infusions; one patient voluntarily withdrew after one infusion because of recurrence of infusion-associated reactions. No anaphylactic reactions occurred. All adverse events, including four serious adverse events, were mild or moderate in intensity. Most treatment-related adverse events occurred during infusions (most commonly urticaria, vomiting, nausea, chills, pruritus, hypertension) and were resolved by infusion rate reductions and/or medication. After participation in the study, all patients, including the one who withdrew after one infusion, transitioned to commercial drug. CONCLUSIONS: Agalsidase beta therapy can be successfully reinstated in patients with Fabry disease who have developed IgE antibodies or skin test reactivity to the recombinant enzyme.

Hypersensitivity reactions to chemotherapeutic drugs.

There is an ever-increasing number of therapeutics used to treat cancer. A recent publication listed 86 currently available antineoplastic medications. Despite this large number, hypersensitivity reactions are not common except with platinum compounds (cisplatin, carboplatin), epipodophyllotoxins (teniposide, etoposide), asparaginase, taxanes (paclitaxel), and procarbazine. Doxorubicin and 6-mercaptopurine are occasionally associated with hypersensitivity reaction. Comparable reactions with other chemotherapeutic agents are. uncommon; many are only anecdotal reports. Reactions associated with individual drugs are discussed in detail. The mechanisms responsible for most of these reactions are not known, as they have generally not been evaluated. The term "hypersensitivity" is widely used in the chemotherapy literature without a common definition. Hypersensitivity is defined here as an unexpected reaction with signs and symptoms not consistent with known toxicity of the drug. Most reactions are coincident with or within hours of drug administration. Almost all are associated with parenteral administration. Symptoms include flushing, alterations in heart rate and blood pressure, dyspnea and bronchospasm, back pain, fever, pruritus, nausea and all types of rashes. Some cases may be due to non-immune mediated release of histamine or cytokines, as many patients can subsequently tolerate re-exposure after pretreatment with steroids and antihistamine, and slow readministration of the drug. This is more compatible with a graded challenge, than desensitization and is generally successful for taxanes, less so for platinum compounds. In most cases hypersensitivity reactions are associated with the specific chemotherapeutic drug. Reaction rates may vary with different forms of the drugs, e.g. pegylated. Occasionally excipients such as Cremaphor EL may induce hypersensitivity reactions.

Hypersensitivity reactions to drugs: evaluation and management.

Most hypersensitivity reactions to drugs occur within several weeks of administration; signs and symptoms are often consistent with known immune-mediated reactions, including anaphylaxis, rashes, fever, cytopenias and vasculitis. The culprit immune mechanisms range from immunoglobulin E antibody to T cells inducing apoptosis of keratinocytes, in the case of bullous exfoliative rashes. Many drugs induce reactions via altered hepatic metabolism, with production of reactive intermediates which induce a common syndrome of rash and fever plus variable types of other signs. Examples of this reactive metabolite syndrome include the rash and fever in HIV-positive patients given sulfamethoxazole and reactions to the aromatic anticonvulsants. With the notable exception of anaphylaxis and severe bullous exfoliative rashes, most immune reactions to drugs are not life-threatening and generally resolve once the drug is discontinued. The key is prevention. Specific immune testing is standardized only for penicillin. If test results are negative, however, the patient can tolerate all beta-lactam antibiotics. Of those patients with a positive penicillin skin test, only 2% develop reactions when given cephalosporins. Sulfa and quinolone antibiotics, and muscle relaxants, also frequently induce reactions. If there is a history of bullous rash, the patient should never again receive sulfa or quinolone, or related drugs. In other cases, a cautious graded challenge or desensitization can be done. Vancomycin, protamine, and radiocontrast media induce non-immune reactions secondary to their irritant effects on vascular endothelium. Narcotic pain medications cause histamine release by binding to a specific receptor on mast cells in sensitive patients. In contrast to true immune reactions, most patients can receive these medications again, if they are pretreated and the drugs are given slowly. Angiotensin-converting enzymes, aspirin, and non-steroidal anti-inflammatory drugs induce adverse reactions by their effect on enzymes. Readministration usually results in repeat symptoms. It is possible to desensitize patients to aspirin. Some patients appear to develop similar adverse symptoms with multiple unrelated drugs. Although these cases present management problems, most patients can complete a therapeutic course of a vital drug, after careful review of the history, immune testing when possible, and graded challenge or desensitization.

Immune reactions to drugs and diagnostic agents.

Adverse reactions to drugs are common, but only a small percentage of these reactions results from a specific immune reaction to a drug. Over-reactivity of almost any part of the immune system can result in an immunologically mediated drug reaction; however, T cell-and immunoglobulin E-mediated reactions are the most common. The reactions are unpredictable and can involve any part of the body, although skin is most frequent. The various pathogenic mechanisms are discussed, along with diagnostic testing, factors predisposing to drug allergy, and reactions to individual drugs and therapeutic reagents.