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PubMed2003

[Preliminary results of monotherapy with thalidomide in recurrent and treatment resistant cases of multiple myeloma].

Thalidomide is an antiangiogenic drug, but its mechanism of action is not well known and demands further studies. The recent literature suggests that thalidomide is an effective drug in multiple myeloma patients. The objective of the study was to estimate the efficacy of thalidomide monotherapy in the treatment of refractory and relapsed cases of multiple myeloma. We treated with thalidomide 17 patients (12 males, 5 females), average age 51 (range 42-73 years), mean time since diagnosis to the start of thalidomide treatment was 24 months (range 5-48). All patients revealed the features of progressive disease. The mean number of prior chemotherapy schemes was 2. Three out of 17 patients received high dose chemotherapy followed by autologous stem cell transplantation. Thalidomide was administered as monotherapy at a dose of 200 mg (n = 8), 300 mg (n = 1) and 400 mg (n = 8). The mean time of drug intake was 3 months (1-12). The criteria of clinical response were decline of paraprotein at least 25%, 50% and 75% in comparison to value before the treatment. In 5 cases (33%) 25% reduction of paraprotein was observed, 1 patient achieved 50% decline. In the responder group a tendency to decrease marrow plasmocytosis, total serum protein, beta M-2 and LDH was noticed. The good tolerance of the drug, especially in lower doses, and lack of myelosuppression effect allows to expect, that the combination of thalidomide with other cytostatic drugs will improve the efficacy in patients with refractory or relapsed myeloma.

Adult↗
PubMed2003

Thalidomide is anti-angiogenic in a xenograft model of neuroblastoma.

Thalidomide has previously been shown to have anti-angiogenic properties. More recently, clinical efficacy of this agent has been demonstrated in multiple myeloma and prostate cancer. Neuroblastoma is the most frequent solid tumor of the abdomen of childhood, yet children with this disease frequently have metastases at presentation. Such patients have a very poor prognosis with current therapies. Thus, new approaches are needed. We have previously shown that VEGF antagonists can inhibit neoangiogenesis and tumor growth in experimental neuroblastoma. In this study, we investigated the anti-angiogenic and anti-tumor properties of thalidomide in a xenograft model of human neuroblastoma. Tumors were induced in athymic mice using the human neuroblastoma cell line NGP. Intraperitoneal thalidomide (100 mg/kg/dose) or vehicle was administered beginning one week after implantation, and animals euthanized at six weeks. Thalidomide treatment did not significantly alter tumor growth as compared with controls. However, thalidomide suppressed angiogenesis, as demonstrated both by fluorescein angiography and immunohistochemical staining, and induced apoptosis of endothelial cells in neuroblastoma xenografts. Quantification of microvessel density demonstrated a significant reduction of vasculature in treated tumors (p<0.004). Thalidomide induced co-option of host vasculature, an effect noted previously after VEGF blockade. This study demonstrates that thalidomide has anti-angiogenic properties in experimental neuroblastoma.

Angiogenesis Inhibitors↗
PubMed2003

[Treatment of erosive oral lichen planus with thalidomide].

INTRODUCTION: Treatment of erosive oral lichen planus is difficult and often requires the use of systemic corticosteroids. This severe condition may lead to weight loss and impairment of patients' general condition due to painful oral erosions. The aim of this study was to evaluate the usefulness of thalidomide in the treatment of severe erosive oral lichen planus. PATIENTS AND METHODS: The efficacy and safety of thalidomide were retrospectively evaluated in 6 patients with severe erosive lichen planus resistant or relapsing despite high doses of oral corticosteroids. Thalidomide was started at an initial dose of 50 to 100 mg/day and was then progressively decreased to the minimal effective dose. Follow-up evaluations were performed every two months by the same dermatologist. RESULTS: Complete healing of erosive lesions was observed in 4 of 6 patients after a mean duration of 4 months. Partial epithelialization of erosive lesions, disappearance of dysphagia and weight gain were observed in one patient. Treatment failed in the last patient. The mean dose of prednisone of the 3 patients receiving both thalidomide and oral corticosteroids decreased from 37 mg/day at the beginning of the study to 7 mg/day at the end of the study. Two patients experienced severe side effects: phlebitis and neuropathy, leading to thalidomide discontinuation. Oral erosions rapidly relapsed after withdrawal of thalidomide. DISCUSSION: Thalidomide seems to be an effective treatment of severe corticosteroid resistant and dependent or when systemic corticosteroids are contraindicated erosive oral lichen planus. Potentially serious side effects should restrict its use to the most severe forms of the disease.

Aged↗
PubMed2004

The effects of thalidomide on the stimulation of NF-kappaB activity and TNF-alpha production by lipopolysaccharide in a human colonic epithelial cell line.

The immunomodulatory and anti-inflammatory effects of thalidomide are associated with inhibition of TNF-alpha levels. However, the mechanism by which thalidomide reduces TNF-alpha production remains elusive. NF-kappaB is known to play a central role in regulating inflammatory responses in patients with inflammatory bowel disease (IBD). We tested whether thalidomide acts through inhibiting NF-kappaB activity. HT-29 cells were stimulated with LPS (1 microg/ml) alone, or after pretreatment with thalidomide (100 microg/ml), and NF-kappaB activity was determined by gel mobility shift assays. RT-PCR was used to measure expression of the proinflammatory cytokine genes TNF-alpha, IL-1beta and IL-8. The level of TNF-alpha mRNA was also analyzed by real-time quantitative RT-PCR, and TNF-alpha protein was measured by ELISA. Thalidomide pretreatment did not affect NF-kappaB activity in HT-29 cells stimulated with LPS but production of TNF-alpha was depressed. Thalidomide was found to accelerate the degradation of TNF-alpha mRNA, but had little effect on IL-1beta or IL-8. These observations suggest that the immunomodulatory effect of thalidomide in colonic epithelial cells is associated with inhibition of TNF-alpha. However, it does not act by inhibiting NF-kappaB but rather by inducing degradation of TNF-alpha mRNA.

Cell Line↗
PubMed2004

Extramedullary multiple myeloma escapes the effect of thalidomide.

BACKGROUND AND OBJECTIVES: Thalidomide is an antiangiogenic drug that produces a response rate ranging from 32 to 64% in patients with refractory/relapsed multiple myeloma (MM). However, the efficacy of thalidomide in patients with soft-tissue plasmacytomas is controversial. The aim of this study was to assess the response rate to thalidomide in patients with advanced MM and to correlate the response rate with the presence of extramedullary involvement. DESIGN AND METHODS: Thirty-eight patients with refractory/relapsed MM were treated with thalidomide. Eleven patients had extramedullary involvement when therapy was initiated. The response rate was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation. RESULTS: Sixteen of the 38 patients (42%) responded to thalidomide. The response rate was significantly higher in patients without extramedullary involvement (59% vs 0%, p=0.0006). Although four of the 11 patients with extramedullary involvement had a serological response, a progression of the soft-tissue masses was observed in all of them. INTERPRETATION AND CONCLUSIONS: Thalidomide is effective in patients with advanced MM. However, extramedullary disease does not respond to thalidomide, as delivered in this series. The mechanisms to explain different response to therapy depending on tumor homing warrant further investigation.

Adult↗
PubMedDate not supplied

Treatment options in colchicine resistant familial Mediterranean fever patients: thalidomide and etanercept as adjunctive agents.

OBJECTIVE: Regular colchicine treatment cannot control the typical febrile attacks of FMF in about 5-10% of the compliant patients. Here we report the effect of thalidomide and etanercept in 5 colchicine-resistant cases. METHODS: Five (4M/ 1F) FMF patients between April 2005 and March 2006, who were experiencing at least 2 attacks per month, despite regular colchicine were included to the study. Four male patients were given thalidomide 100 mg/d initially. Two of these patients unresponsive to thalidomide were prescribed subcutaneous injections of etanercept 25 mg, twice a week. The female patient received etanercept as the first choice due to potential side effects. She then had to be converted to thalidomide due to a severe injection site reaction. RESULTS: The median follow up period with thalidomide and etanercept was 8 months. Both thalidomide and etanercept lowered the number of the abdominal attacks. CONCLUSION: Thalidomide and etanercept might be effective as additional treatment in colchicine-resistant cases of FMF.

Adult↗
PubMedDate not supplied

Thalidomide plus monthly high-dose dexamethasone in chemorefractory myeloma. Results of a phase II clinical study.

Thalidomide is a potent anti-myeloma drug which can produce up to a 30-50% overall response rate (ORR) in pre-treated, chemorefractory multiple myeloma. Most authors agree with using 200 mg/daily with associated high dose dexamethasone (40 mg/daily x 4 days, 3 times monthly) considering lower doses investigational. We report our experience using thalidomide 100 mg/daily plus dexamethasone 40 mg/daily once a month, in 27 pre-treated patients. Thalidomide dose excalation and/or association with other drugs were established on the basis of the patient's response. Median age was 69 years (range 50-83 years) and 16 male and 11 female patients were treated. All patients had received more than 1 treatment line (range 1-5). Thalidomide was increased up to 300 mg/daily in 10 patients and 1 patient received up to 400 mg/daily. Two patients were not evaluable because of early death, 1 did not tolerate thalidomide because of pulmonary and neurological side-effects. Sixteen patients responded to this treatment, with an ORR of 66%. The combination of low-dose thalidomide plus monthly high-dose dexamethasone in chemorefractory myeloma showed interesting palliative results. According to our data, increasing thalidomide dosage and/or adding further drugs does not generally produce significant improvement.

Aged↗
PubMed2006

[Positive immunoregulation of thalidomide on human peripheral blood mononuclear cell cultures].

This study was purposed to investigate the effects of thalidomide on proliferation of peripheral blood mononuclear cells (PBMNCs), levels of lymphocyte subsets, secretion of cytokines and its killing activity, and to elucidate the immunoregulation mechanisms in treatment of multiple myeloma with thalidomide. The method of MTT was used to detect the effects of thalidomide on the proliferations and the cytotoxic activity of PBMNC; the flow cytometer was used to analyze the lymphocyte subsets; the ELISA was used to measure the concentrations of cytokines in culture supernatants. The results showed that thalidomide enhanced the proliferations of the CD8+ T, NK cells in PHA-stimulated PBMNC from healthy volunteers, increased the secretion of IL-6 significantly, and decreased the secretion of IFN-gamma, and the secretions of IL-2 and IL-10 were not affected. Compared with control group, at the same ratio of effectors to targets the thalidomide (5 microg/ml) could enhance the cytotoxic activity of PBMNC (P < 0.01), the cytotoxic activity was maximal when the ratio of effectors to targets was 40:1. It is concluded that thalidomide preferentially enhances the proliferations of CD8+ T, NK cells in PHA-stimulated PBMNC from healthy volunteers, and enhances the cytotoxic activity of PBMNC by increasing the secretion of IL-6 significantly, in short, thalidomide can exert anti-myeloma effects by increasing cellular immune function.

Adjuvants, Immunologic↗
PubMed2003

Successful treatment with low-dose thalidomide in a patient with both Behçet's disease and complex regional pain syndrome type I: case report.

Thalidomide is a recognized treatment of Behçet's disease. Low-dose thalidomide seems to be effective in the treatment of orogenital ulcers and is potentially safer with a lower incidence of adverse effects than higher doses. We wish to report a case of Behçet's disease in a 33-year-old woman who responded well to thalidomide 50 mg 2 to 4 times per week. Her disease manifestations (severe orogenital ulceration, pseudofolliculitis, mild thrombophlebitis, positive pathergy response, and fatigue) were previously resistant to courses of prednisone, dapsone, colchicine, various types of mouthwash, and topical steroid preparations. She also gave a history of complex regional pain syndrome type I (CRPS 1) over her left patella (severe pain, intermittent edema, hyperalgesia, allodynia, cold skin, and loss of movement) after a fall onto her left knee 6 years previously. This had only partially responded to a variety of treatment modalities. After starting thalidomide for her Behçet's disease, the pain in her left knee unexpectedly disappeared. There are rat experiments showing that thalidomide improves neuropathic pain, probably by selectively blocking tumor necrosis factor-alpha production in activated macrophages. We believe this is the first report of successful use of thalidomide in a human being with CRPS 1, and we therefore recommend that thalidomide should be considered in the treatment of CRPS 1.

Journal Article↗
PubMed2002

Antitumorigenic Evaluation of Thalidomide Alone and in Combination with Cisplatin in DBA2/J Mice.

Thalidomide's reported ability to inhibit angiogenesis has led to clinical trials determining its effectiveness in combating various types of cancer. This study explored thalidomide's antitumorigenic potential when administered alone and in combination with cisplatin to DBA2/J mice whose tumors were induced by murine erythroleukemic cells. Thalidomide treatment alone produced no significant inhibitory effect on tumor development and metastasis. Mice that received both drugs had significantly lower incidences of both primary and secondary tumors as compared to the untreated control group. Cisplatin, administered alone or in combination with thalidomide, led to a significant delay in tumor formation and a longer life span than was recorded in untreated mice. However, the combination treatment results were not significantly different from those of cisplatin treatment used as a single agent. In in vitro cell multiplication studies using murine erythroleukemic and murine endothelial cells, thalidomide failed to inhibit cell proliferation. However, cisplatin treatment with or without thalidomide, significantly inhibited the multiplication of both cell lines in a dose dependent manner. Thalidomide does not appear to be a beneficial adjuvant to cisplatin treatment.

Journal Article↗
PubMed2002

Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients.

Thalidomide is effective in several cutaneous diseases. Peripheral neuropathy is the most important adverse event limiting its use. Its incidence rate and its relation to thalidomide doses remain unclear. We prospectively monitored 135 patients treated with thalidomide for various dermatologic diseases for 2 y in order to estimate the annual incidence rate and risk factors for neuropathy. Patients underwent standardized neurologic examination and nerve conduction studies prior to, and regularly during treatment. Risk factors for neuropathy were assessed using a Cox proportional-hazards model. Clinical and electrophysiologic evidence of a thalidomide-induced neuropathy were present in 25.2% of the patients; however, when considering all potential cases, this rate reached 55.6%. The incidence rate was maximal during the first year of treatment (20%). The risk of neuropathy was related to the daily dose whatever the duration of treatment (p<10-3). Considering a daily dose < or =50 mg per day as reference, the relative risk for thalidomide neuropathy was 8.2 for a daily dose comprised between 50 and 75 mg per day and 20.2 for a daily dose >75 mg per day (p<10-3). No neuropathy occurred for daily doses < or =25 mg per day. The neuropathy was subclinical in nearly a quarter of patients with such an adverse event. These data confirm the high rate of thalidomide neuropathy and identify the daily dose as the main risk factor. The risk of neuropathy seems to be negligible for doses less than 25 mg per day, whatever the duration of therapy.

Adult↗
PubMed2000

Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women.

The effect of food on the oral pharmacokinetics of thalidomide and the relative bioavailability of two oral thalidomide formulations were determined in an open label, single dose, randomized, three-way crossover study. Five male and eight female healthy volunteers received a single oral dose of 200 mg Celgene thalidomide capsules under fasted and non-fasted conditions, and a single dose of 200 mg tablets of Serral thalidomide under fasted conditions. The high-fat meal resulted in a 0.5-1.5 h absorption lag time, an increased mean C(max), a decreased mean AUC and a delay in mean T(max). The Serral tablet formulation resulted in a lower mean C(max), and slower terminal decline in plasma thalidomide concentrations compared with both Celgene treatments. Mean C(max) concentrations were 1.99+/-0.41 microg/mL (range 1.28-2.76) within 4.00+/-1.13 h (2-5) for the Celgene formulation fasted, 2.17+/-0.51 microg/mL (1.43-3.01) within 6.08+/-2.33 h (3-12) for the Celgene formulation with food, and 1. 05+/-0.31 microg/mL (0.62-1.65) within 6.23+/-1.88 h (5-10) for the Serral formulation fasted. Mean terminal half-lives were 13.50+/-6. 77 h for the Serral product, compared with 5.80+/-1.72 h and 5. 09+/-1.03 h for Celgene fasted and fed, respectively. Celgene's formulation exhibited slightly greater bioavailability than Serral's formulation, with mean ratios of 122% and 110% for Ln-transformed AUC(0-t) and AUC(0-infinity), respectively. The mean C(max) for the Celgene formulation was approximately two times greater than Serral's. Food delayed the onset of absorption of by 0.5-1.5 h, but had little effect on the extent of absorption from the Celgene capsule. Under fasted conditions, the Celgene thalidomide resulted in a two-fold greater C(max) and 10% greater AUC(0-infinity) than the Serral formulation.

Administration, Oral↗
PubMed2004

Effects of thalidomide on reproductive function and early embryonic development in male and female New Zealand white rabbits.

BACKGROUND: The present work was performed to determine the effect of thalidomide exposure on reproductive function and early embryonic development. METHODS: Twenty-five female New Zealand White rabbits were orally gavaged with 0, 10, 50, or 100 mg/kg/day thalidomide 14 days prior to mating through to gestation day 7 for a total of 22 days. Treated females were Caesarean-sectioned approximately 29 days after the date of attempted mating. Following mating with treated females, male rabbits (25/dose) were gavaged with 0, 30, 150, or 500 mg/kg/day beginning 14 days prior to mating with a group of untreated females (25/dose). Doses were administered through mating until the day before sacrifice for a minimum of 56 days. Untreated females were Caesarean-sectioned 29 days after the last attempted mating. Comprehensive necropsy and histopathology of the reproductive system were performed. RESULTS: Treated females had reduction in body weight gain during gestation. Mating and pregnancy parameters were unaffected by thalidomide. At 100 m/kg, litter averages for corpora lutea, implantations, litter sizes, does with viable fetuses and live fetuses decreased and the number of early resorptions, does with any resorptions, does with all conceptuses resorbed, and the percent resorbed conceptuses per litter increased. The number of early resorptions, the average number of early resorptions per litter, and the percent resorbed conceptuses per litter increased at 10 and 50 mg/kg. There were no thalidomide-related external fetal malformations. Mating and fertility in male rabbits were unaffected by thalidomide. There was an increased incidence of flaccid testes at 150 and 500 mg/kg and of bilateral small testes in all treated groups. At 500 mg/kg, there was degeneration of the germinal epithelium of the testicles with an increase in multinucleated giant cells in seminiferous tubule and a loss of round and elongating spermatids. CONCLUSIONS: Thalidomide had no adverse effects on mating and fertility in male and female rabbits dosed up to 500 and 100 mg/kg/day, respectively, for 14 days prior to mating. After 56 day of dosing, histopathologic changes with no associated sperm abnormalities were observed in the testicles. Embryonic development NOAEL for treated females mated to untreated males was <10 mg/kg. Corresponding fertility NOAEL for treated males mated to untreated females was 500 mg/kg.

Aborted Fetus↗
PubMed2002

A pilot study of thalidomide in patients with progressive metastatic renal cell carcinoma.

BACKGROUND: The highly vascular nature of renal cell carcinoma (RCC) suggests that angiogenesis inhibition may be therapeutic for patients with this disease. Thalidomide inhibits basic fibroblast growth factor and vascular endothelial growth factor (VEGF)-induced angiogenesis. METHODS: In a pilot study, we evaluated the safety and efficacy of escalating doses of thalidomide in patients with progressive metastatic RCC (mRCC), measurable disease, and good organ function. Patients received oral thalidomide starting at 200 mg per day and increasing by 100-200 mg per day weekly until a target dose of 1200 mg per day was reached. Study endpoints were objective tumor response and toxicity. RESULTS: Of the 20 patients enrolled, 19 were evaluable for response. Eighteen achieved the target dose. The most common, but reversible, toxicities were constipation, somnolence, and fatigue. Peripheral neuropathy was seen after prolonged therapy, necessitating dose reduction. Two patients achieved a partial response and nine had stable disease for a median of 14 months (range, 3-17 months). Median time to progression was 4.7 months (range, 0.7-31.3 months). Fifteen patients died (median survival, 18.1 months; 95% lower confidence bound 10.7). Survival was significantly longer in patients with higher hemoglobin level and longer time from first metastasis to start of thalidomide, but significantly shorter in patients with multiple organ involvement and previous treatments. CONCLUSIONS: Thalidomide at this dose is associated with manageable acute toxicities but long-term dose-limiting neuropathy. Objective responses are rare in patients with mRCC and are characterized by delay in achieving maximum tumor reduction. Prolonged stable disease is seen in some patients, but the benefit of thalidomide, as well as other angiogenesis inhibitors, in that setting needs to be studied in controlled, randomized trials.

Administration, Oral↗
PubMed2004

Thalidomide reduces serum C-reactive protein and interleukin-6 and induces response to IL-2 in a fraction of metastatic renal cell cancer patients who failed IL-2-based therapy.

Interleukin-2 (IL-2) has some antitumor activity in patients with renal cell carcinoma. It has been noted that response to IL-2 and prognosis may be adversely affected by elevated serum levels of C-reactive protein (CRP) or interleukin-6 (IL-6). We used thalidomide to treat patients with cancer-induced cachexia and noted that the drug significantly reduced serum levels of CRP and IL-6 to normal or near normal levels in a substantial fraction of patients. We tested whether thalidomide might potentiate the response of patients with renal cell carcinoma to IL-2. Four patients with metastatic renal cell carcinoma and high serum levels of CRP and IL-6 who had experienced disease progression on IL-2 were retreated with the same IL-2 regimen combined with thalidomide 300 mg p.o. daily. Two patients achieved good partial responses and 2 patients had prolonged disease stabilization with the combination of IL-2 plus thalidomide. The regimen was well tolerated without increased IL-2-associated toxicity. Reduction of serum CRP or IL-6 levels with thalidomide may enhance the responsiveness of renal cell carcinoma to IL-2. A Phase II study of the combination is in order. It is possible that the thalidomide-induced normalization of serum acute phase proteins might improve the response of other types of malignancy to IL-2 or other immune-based therapies.

Adult↗
PubMed2007

A phase II trial using thalidomide for Langerhans cell histiocytosis.

BACKGROUND: Few new drugs for treatment of Langerhans cell histiocytosis (LCH) have been studied. Tumor necrosis factor-alpha (TNF-alpha) is a prime therapeutic target since it appears to be present in elevated amounts in LCH lesions. Thalidomide inhibits TNF-alpha production by affecting the gene promoter as well as other anti-cytokine effects. PROCEDURES: A Phase II trial of thalidomide for treatment of LCH patients who had failed primary and at least one secondary regimen was conducted. Sixteen patients were enrolled: nine males and seven females ranging in age from 19 months to 45 years. Six patients were high risk (HR) because of spleen, liver, lung, or bone marrow involvement. The low risk (LR) patients included six with bone/skin LCH, one with multiple bone, one with skin/bone/pituitary, one with skin/bone/brain, and one with skin only disease involvement. Fifteen patients remained on treatment from 3 weeks to over 1 year. RESULTS: Among the LR patients there were four complete responses, three partial responses, and two with no response to thalidomide. No HR patient responded to thalidomide and all died of pulmonary, liver, or bone marrow failure. Thalidomide may have played a role in the pulmonary failure. Other toxicities that required stopping therapy included neutropenia, peripheral neuropathy, and fatigue. CONCLUSIONS: Thalidomide is an effective therapy for some LR patients with LCH, but showed no significant responses in HR patients. Dose-limiting toxicities may reduce its efficacy in LR patients. Additional trials with improved anti-TNF therapies would appear warranted.

Adolescent↗
PubMed1997

Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization.

Thalidomide, when administered orally, is an inhibitor of angiogenesis in the basic fibroblast growth factor (bFGF)-induced rabbit cornea micropocket assay. We now show in the mouse that thalidomide given intraperitoneally but not orally significantly inhibits bFGF-induced and vascular endothelial growth factor (VEGF)-induced corneal neovascularization. We further demonstrate that this inhibition is independent from thalidomide's ability to suppress tumor necrosis factor-alpha (TNF-alpha) production. Experiments examining thalidomide's enantiomers reveal-that the S(-)-enantiomer has the strongest antiangiogenic activity in VEGF-induced and bFGF-induced corneal neovascularization. Structure activity studies suggest that thalidomide's anti-angiogenic activity is related to the open ring metabolites resulting from hydrolysis. Together these data support a correlation between thalidomide's antiangiogenic and teratogenic activities.

Administration, Oral↗
PubMed1996

Thalidomide inhibits TNF response and increases survival following endotoxin injection in rats.

Sepsis is a leading cause of death following major trauma and complicated abdominal surgery. Tumor necrosis factor-alpha (TNF) is believed to be a central mediator in the inflammatory response syndrome. Numerous methods of blunting the TNF response in sepsis have been attempted with suggestion of increased survival and decreased organ injury. Thalidomide, shown in vitro to selectively inhibit TNF production, has been used clinically in states of chronic TNF elevation with encouraging results. In this study, we examined the effect of thalidomide administration in a rat model of acute septic shock. Femoral artery cannulation was performed and baseline TNF measured. Dose response was determined by giving varying doses of thalidomide by gavage. Rats were injected intraarterially with endotoxin and serial samples drawn. TNF was measured by ELISA. For survival, thalidomide was given by gavage and endotoxin injected intraperitoneally. Serum TNF elevation occurred after endotoxin injection with peak levels at 90 min. Thalidomide treated rats had lower TNF levels at all time points (P = <0.01 at 90 and 120 min), with the inhibition being dose dependent. Survival in treated rats exceeded that of untreated rats (53% vs 19%, P = <0.05) at 48 and 72 hr. In conclusion, we found that thalidomide administration leads to increased survival following acute endotoxemia, which may be due to the observed TNF inhibition.

Analysis of Variance↗