Tumor necrosis factor alfa

Since the first reports of hypothyroidism, a number of studies have reported the occurrence of thyroid dysfunction in patients receiving aldesleukin alone or in combination with LAK cells, interferon alfa, interferon gamma, or tumor necrosis factor alfa (SED-13, 1104 6). Symptoms were usually observed after 2-4 months of treatment (7-9), and mostly consisted of moderate hypothyroidism, which resolved after immunotherapy withdrawal or thyroxine treatment (9,10). Patients treated with aldesleukin plus interferon alfa more commonly developed biphasic thyroiditis with subsequent hypothyroidism or hyperthyroidism (10-13). 

The underlying mechanism may involve the adipose tissue hormone leptin or immune modulators such as tumor necrosis factor alfa. 

Exacerbation of hypothyroidism was noted in one patient with chronic thyroiditis who received tumor necrosis factor alfa (1153). 

Metabolic effects of tumor necrosis factor alfa include a reduction in cholesterol and high-density lipoproteins, increases in triglycerides and very low-density lipoproteins, and hyperglycemia. 

The mechanism by which the systemic administration of interferon alfa produces neurotoxicity is unclear, and might result from a complex of direct and indirect effects involving the brain vasculature, neuroendocrine system, neurotransmitters and the secondary cytokine cascade with cytokines which exert effects on the nervous system, for example interleukin-1, interleukin-2, or tumor necrosis factor alfa (363). Whether a clinical effect is directly mediated through the action of a given cytokine or results from a secondary pathway through the induction of other cytokines or second messengers is difficult to determine. 

Evaluation of cognitive function in patients receiving tumor necrosis factor alfa alone or combined with inter-leukin-2 showed reversible attentional deficits, memory disorders, deficits in motor coordination and frontal lobe executive functions (661). There was reversible hypoperfusion in the frontal lobes. 

Because soluble tumor necrosis factor alfa receptors are supposedly involved in the macrophage activation syndrome, the authors speculated that the administration of additional soluble receptors may have been the cause of a prolonged and exacerbated syndrome. 

In contrast to infliximab, etanercept is rarely associated with severe infectious complications. This has been attributed to different mechanisms of tumor necrosis factor alfa neutralization by the two drugs. Indeed, only nine cases of tuberculosis have previously been reported to the FDA from more than 100 000 patients treated worldwide (30). However, severe or uncommon infectious complications (severe viral pneumonia, fatal pneumococcal sepsis due to... 

The authors speculated that the most likely explanation for these observations was linked to the lack of transfer of high-molecular weight soluble receptors and IgG across the blood-brain barrier, implying that control of brain tumor necrosis factor alfa cannot be obtained with monoclonal antibodies. They thought that neurological complications in diseases other than multiple sclerosis might be related to control of tumor necrosis factor alfa in the periphery, resulting in an enhanced contribution of brain-derived tumor necrosis factor alfa or other cytokines, such as interleukin-1. 

Infliximab binds to tumor necrosis factor alfa on cell surfaces and produces apoptotic cell death, releasing the nucleosomal autoantigens that induce autoantibody formation (28). 

Blockade of tumor necrosis factor alfa impairs resistance to infections with intracellular pathogens such as mycobacteria, Pneumocystis proved. Listeria monocytogenes,... 

There is great concern about the potential development of malignancy after blockade of tumor necrosis factor alfa, and it is biologically plausible. However, it is unclear whether this is a drug-related or a disease-related phenomenon. 

A77 1726 inhibits dihydro-rate dehydrogenase, the rate-limiting enzyme in pyrimidine synthesis. It inhibits the proliferation of T and B cells, and probably acts via the production and action of interleukin-2. Besides its immunomodulatory action, A77 1726 also has an antiinflammatory action by inhibition of nuclear factor kappa B (NFkB), tumor necrosis factor alfa (TNF-a),... 

Although the release of a wide range of cytokines was increased after muromonab administration, tumor necrosis factor alfa and interleukin-6 were suggested to play a pivotal role, and monoclonal anti-TNF-alfa antibody administration reduced the acute chnical symptoms (15). A role for the activation of complement and neutrophils was also suggested. 

Cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor alfa influence bone resorption and have been invoked as a cause of type 1 osteoporosis. 

Parenteral nutrition in experimental rats enhances the catabolic effect of tumor necrosis factor alfa (119). The role of parenteral nutrition-induced cjdokine release or activity, especially of IL-1, IL-6, and tumor necrosis factor alfa, in causing hypercalciuria and reduced mineralization in patients receiving parenteral nutrition needs to be clarified (119). 

Pentoxifylline (oxipentifylline) is a methylxanthine that antagonizes the vasoconstrictor effects of catecholamines and increases cyclic AMP concentrations, causing smooth muscle to relax. It has also been claimed to correct impaired microcirculation, by improving various factors that disturb blood rheology, and to reduce the generation of toxic free radicals from leukocytes during ischemic leg exercise in patients with intermittent claudication. Pentoxifylline has been used to suppress overproduction of tumor necrosis factor alfa in conditions such as falciparum malaria and rheumatoid arthritis and in transplant recipients, with varied success. 

In 52 adults with cerebral malaria who were randomized to either quinine dihydrochloride alone (n = 32) or a combination of quinine and pentoxifylhne (n = 20), the addition of pentoxifyUine significantly improved coma resolution time from 64 to 22 hours and reduced mortality from 25% to 10% (1). Three days after therapy, serum tumor necrosis factor alfa concentrations fell significantly in those who received pentoxifylline. Pentoxifylline caused no serious adverse effects that necessitated withdrawal. 

In an open, randomized, controlled trial in 56 children with cerebral malaria, the 26 children who received pentoxifylline 10 mg/kg/day by continuous infusion had significantly shorter periods of coma than the controls. The pentoxifylline recipients showed a trend toward a lower mortality. Pentoxifylline has an inhibitory effect on the synthesis of tumor necrosis factor alfa. The better outcome in the treated group was associated with a fall in tumor necrosis factor alfa serum concentrations on the third day of treatment in a few subjects this was not seen in the controls (7). 

However, in a later, randomized, placebo-controlled trial pentoxifyUine neither reduced tumor necrosis factor alfa serum concentrations nor affected the clinical course in 51 patients who received it as adjunctive treatment to standard antimalarial therapy in a dosage of 20 mg/kg/day over 5 days (8). 

Oxaliplatin is generally well tolerated. Some patients develop fever, which appears to be related to a transient increase in cytokines, particnlarly interlenkin-6 and tnmor necrosis factor alfa. In one stndy the oxaliplatin-induced increase in body temperatnre correlated with a marked increase in interlenkin-6 sernm concentrations (peak 133 pg/ml) (251). Interlenkin-6 is a proinflamma-tory cytokine, which stimnlates acnte phase proteins and B lymphocytes. Premedication with metamizol, dexamethasone, and clarithromycin, which interferes with interleukin-6, did not prevent the fever. The roles of interleukin-6 and tumor necrosis factor alfa in the development of fever is strengthened by the observation that their serum concentrations fell during resolution of the fever (252). 

Of 52 patients with colorectal cancer treated with a median of six 3-weekly cycles of raltitrexed 1.5-3.0 mg/m combined with oral carmofur 300-400 mg/m on cycle days 2-14, 39 had a fever on days 2-9 after receiving raltitrexed, 49 had fatigue, and 49 had a raised serum C-reactive protein concentration without a documented infection (6). Median concentrations of C-reactive protein, interleukin-6, interleukm-8, and tumor necrosis factor-alfa were higher 7 days after raltitrexed or raltitrexed + carmofur than at baseline. The authors suggested that patients with colorectal cancer treated with raltitrexed may develop drug-related systemic inflammation, which may be difficult to distinguish from infection. 

Hypotension, perhaps nitrous oxide-mediated, is a dose-limiting adverse effect of tumor necrosis factor alfa (5). 

Severe hypophosphatemia with myocardial dysfunction was noted in patients receiving tumor necrosis factor alfa by continuous hepatic arterial infusion (SEDA-17, 433). 

Congestive cardiomyopathy has been attributed to tumor necrosis factor alfa in isolated patients (SED-13, 1110) (6). 

Tumor necrosis factor alfa is considered to be a major neurotoxic agent, and most patients who received large doses developed central nervous system symptoms, most commonly headache, lethargy, fatigue, confusion, disorientation, and reduced performance. Seizures, transient amnesia, aphasia, hallucinations, and diplopia sometimes occur (9). 

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