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PubMed1988

Thalidomide for treatment of graft-versus-host disease.

We have used thalidomide in a rat major MHC mismatch model of graft-versus-host disease (GVHD). When given prophylactically, most animals do not develop GVHD and those developing mild GVHD respond to continued therapy. Treatment of established acute GVHD, likewise, was successful. In both prophylactic and therapeutic administration, animals did not develop GVHD after drug cessation. Animals were shown to be stable chimeras by acceptance of donor strain skin grafts and mixed lymphocyte cultures (no response to donor or recipient strain while responding to third party strain). Treatment of chronic GVHD in this model has shown thalidomide to be better tolerated and more successful than cyclosporine (CSA) or prednisone plus azathioprine. The mechanism of action of thalidomide has been explored using a fluorescent thalidomide derivative. These studies have shown striking similarities between thalidomide and CSA. Both drugs appear to allow the development of antigen specific suppressor cells while inhibiting the development of precursor cytotoxic cells. Because of these encouraging results, we have begun a phase I/II trial of thalidomide in refractory GVHD. The preliminary results are encouraging.

Animals↗
PubMed1995

The effect of thalidomide on BCG-induced granulomas in mice.

Granuloma proliferation is the result of a series of complex biological events in which a variety of cell types and cytokines are involved. Tumor necrosis factor alpha (TNF-alpha) plays a central role. In the present study, we investigated the effect of thalidomide (alpha-N-pthalimidoglutarimide), a selective inhibitor of TNF-alpha synthesis, on granuloma formation during BCG infection in Oncins France 1 (OF-1) mice. Subcutaneous injections of 30 mg/kg body weight of thalidomide daily for 14, 21 or 28 days into the mice resulted in the reduction of the size and total number of liver granulomas. The most striking effect of thalidomide was observed after 28 days, when the total number of liver granulomas was reduced by as much as 40% (P < 0.05). Serum TNF-alpha levels of thalidomide-treated mice were significantly lower (85%) than control mice on day 14 and remained lower (55%) on days 21 and 28. Positive immunohistochemical staining specific for TNF-alpha were demonstrable only in well-developed granulomas in which central mononuclear cells presented extensive differentiation into epithelioid cells. Daily administration of thalidomide for 21 to 28 days to the BCG-infected mice inhibited local TNF-alpha expression in well-developed granulomas. The mechanisms by which thalidomide modulates the granuloma proliferation are discussed.

Animals↗
PubMed1997

Inhibition of IL-12 production by thalidomide.

The immunomodulatory properties of thalidomide are currently being exploited therapeutically in conditions as diverse as erythema nodosum leprosum, chronic graft-vs-host disease, rheumatoid arthritis, and sarcoidosis. The relevant mechanism of action of thalidomide in these diseases remains unclear. The important role recently ascribed to IL-12, a cytokine critical to the development of cellular immune responses, in the pathogenesis of several of these conditions led us to examine whether thalidomide affects the production of IL-12. Thalidomide potently suppressed the production of IL-12 from human PBMC and primary human monocytes in a concentration-dependent manner. Thalidomide-induced inhibition of IL-12 production was additive to that induced by suboptimal inhibiting doses of dexamethasone, and occurred by a mechanism independent of known endogenous inhibitors of IL-12 production. These results suggest that thalidomide may have therapeutic utility in a wide range of immunologic disorders that are characterized by inappropriate cellular immune responses.

Antibodies, Monoclonal↗
PubMed1998

The effect of thalidomide and 2 analogs on collagen induced arthritis.

OBJECTIVE: Thalidomide has been described as an inhibitor of both angiogenesis (which may account for its teratogenic effects on limb bud formation) and tumor necrosis factor-alpha (TNF-alpha) production. We evaluated its therapeutic potential in collagen induced arthritis (CIA), a rat model of rheumatoid arthritis (RA). METHODS: Rats were administered orally 200 mg/kg/day thalidomide (n = 10) or either of 2 analogs, EM-12 (n = 9) or supidimide (n = 9). An additional group was given thalidomide (n = 10) at 200 mg/kg twice daily, and a control group (n = 13) was given vehicle only. At completion of the protocols, serum levels of TNF-alpha and vascular endothelial growth factor (VEGF) were measured. RESULTS: Suppression of inflammatory synovitis by clinical and radiographic criteria was significantly lower in all experimental protocols except the lower dose thalidomide group. The EM-12 analog was the most efficacious, and twice daily thalidomide was better than once daily. The incidence of arthritis onset was comparable among all groups. Strong cell mediated and humoral responses to type II collagen, measured by a radiometric delayed type hypersensitivity assay and anti-type II collagen IgG ELISA, respectively, were similar in the experimental and control groups. TNF-alpha and VEGF levels were increased in all rats immunized with collagen compared to naive controls. CONCLUSION: Thalidomide and its analogs can suppress the clinical severity of rat CIA, but the mechanism of action is not a result of TNF-alpha or VEGF downregulation.

Animals↗
PubMed1999

Long-term remission of Crohn's disease treated with thalidomide: a seminal case report.

A 31-year-old female with severe Crohn's disease for 15 years who had been treated with corticosteroids and 6-mercaptopurine, was treated with thalidomide initially for erythema nodosum. While on thalidomide all symptoms of Crohn's disease disappeared and she was able to discontinue all other drugs. At this writing she has been on thalidomide as sole therapy for over 4 years with the exception of a 5-week hiatus, during which time her symptoms recurred, but again disappeared after resumption of thalidomide therapy. This case suggests that thalidomide may be a useful therapy for Crohn's disease and provides impetus for a clinical trial of thalidomide for Crohn's disease.

Journal Article↗
PubMed2000

Pilot and safety trial of carboplatin, paclitaxel, and thalidomide in advanced non small-cell lung cancer.

We performed a pilot study to assess the safety of thalidomide in combination with standard chemo-therapy in patients with advanced non small-cell lung cancer. Patients with unresectable stage IIIA, IIIB, or IV disease were enrolled starting in July 1999. Patients received paclitaxel 225 mg/m2 over 3 hours and carboplatin area under the curve = 6.0 with thalidomide at a starting daily dose of 200 mg. The thalidomide dose was escalated, if tolerated, by 200 mg per week to a target dose of 1000 mg per day and could continue for up to 6 months. Patients with stages IIIA and IIIB disease without effusion received radiotherapy with concurrent thalidomide after 2 cycles of chemotherapy. Nine patients were enrolled: one with IIIA disease, three with IIIB disease, and five with stage IV disease. Five of nine patients had previously been treated with chemotherapy and/or radiotherapy. The most frequent side effects noted were fatigue, myalgia, constipation, neuropathy, and myelosuppression. Sixteen of the 17 (94%) episodes of grade 3 or 4 hematologic toxicity occurred in the five patients who had previously received chemotherapy, although no patients developed neutropenic fever. The median tolerated daily thalidomide dose was 600 mg. One patient with IIIA disease had a partial response after 2 cycles of chemotherapy and went on to receive radiotherapy with thalidomide. One patient with stage IV disease continues on this study with stable disease at 187 days. The median time to progression was 118 days. This preliminary data supports the further investigation of this combination in chemotherapy-naive patients with advanced non small-cell lung cancer.

Journal Article↗
PubMed2003

[Thalidomide: Drug of horror and last resort. A review. Part 1: Origin, molecular structure and first pattern of use.].

Thalidomide was originally a hypnotic, sedative and anxiolytic drug that was first used in 1955. It was considered to have little toxicity and have smooth activity. Thalidomide was in fact poorly studied both in animals and for therapeutic purposes. It was nevertheless agressively advertised, and inter alia for use in pregnancy, and accordingly it was a much used drug. During the year 1961 it became evident that intake of thalidomide in therapeutic doses could result in severe peripheral neuritis and, when taken early in pregnancy, in horrendous damage to the fetus. Thalidomide was thus shortly afterwards generally removed from the market and its use prohibited. Nevertheless, interest rose a few years later to use thalidomide on other indications than before. This is the topic of Part 2 of this review as well as discussion of studies pertinent to the mechanisms of action of thalidomide.

English Abstract↗
PubMed2004

Thalidomide treatment for prurigo nodularis in human immunodeficiency virus-infected subjects: efficacy and risk of neuropathy.

OBJECTIVE: To evaluate safety and efficacy of thalidomide in the treatment of prurigo nodularis in a group of human immunodeficiency virus (HIV)-infected patients whose condition was recalcitrant to standard treatment. DESIGN: Prospective study. SETTING: Outpatient dermatology and neurology clinic, both referral settings. PATIENTS: Eight HIV-infected patients with refractory prurigo nodularis; a total of 10 met inclusion criteria, but 2 could not be followed up. INTERVENTIONS: Treatment with thalidomide, 100 mg/d. Subjects were randomized after 1 month to receive 100 or 200 mg/d. If side effects were noted, the drug was reduced to a tolerable dose or discontinued. Subjects were monitored at baseline and monthly for degree of pruritus and total area of body involvement of prurigo nodularis. Sequential neurologic assessments were performed. MAIN OUTCOME MEASURES: Efficacy and toxic effects. RESULTS: The dosage of thalidomide ranged from 33 to 200 mg/d. Eight subjects had a greater than 50% response in reduction of itch over 3.4 months (average). Seven subjects had a greater than 50% reduction of skin involvement over 5 months (average). Three subjects developed thalidomide peripheral neuropathy (TPN). There was no correlation between duration of treatment, daily or cumulative dose, and TPN. A change in the Neuropathy Impairment Score of 10 points was a good marker of TPN, as was a greater than 50% decrease in the sural sensory nerve action potential amplitude. CONCLUSIONS: Thalidomide reduced the signs and symptoms of prurigo nodularis in HIV-infected subjects. One third of subjects developed TPN, underscoring the importance of careful neurologic assessment.

Administration, Oral↗
PubMed1997

The return of thalidomide: are birth defects surveillance systems ready?

In the 1960s, thalidomide caused limb deficiencies in thousands of infants worldwide. The limb deficiencies were frequently of the intercalary type. As a result, numerous countries started birth defect surveillance programs. In 1967, the Centers for Disease Control (CDC) started the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based surveillance system, to provide early warning against new teratogens. Recent studies have shown that thalidomide may be beneficial for a range of conditions, including cancer and AIDS, and it may once again become widely available. Here, we examine the ability of MACDP to detect an increase in the birth prevalence of limb deficiency as an early warning of fetal exposure to thalidomide. We calculated base rates for all limb deficiencies, for bilateral nonsyndromic intercalary or preaxial deficiencies, and for all nonsyndromic intercalary limb deficiencies among Atlanta infants born from 1968 through 1993. We used relative risk estimates from previous studies and a range of pregnancy exposure rates for thalidomide. We tested the statistical power of MACDP to detect subtle changes in the birth prevalence of these defects using Poisson and cumulative sum (CUSUM) techniques. The base rates for all limb deficiencies, for bilateral intercalary or preaxial deficiencies, and for all intercalary limb deficiencies, were 0.53, 0.035, and 0.022/1,000, and the estimated relative risks were 175, 4,570, and 8,180, respectively. We varied the assumed rate of exposure to thalidomide from 1/10,000 to 5/100. With a 1/1,000 exposure rate, both Poisson and CUSUM techniques will detect a rate change in intercalary limb deficiency in about 6 months of monitoring, and a rate change in bilateral intercalary or preaxial deficiencies in about 12 months of monitoring. When monitoring all limb deficiencies, a pregnancy exposure rate of 3.5% or less would go unnoticed by the Poisson method and would take more than 50 years for the CUSUM method to signal an alarm with a 1/1,000 exposure rate. However, for rates of exposure less than 1/1,000, a progressively longer period of time or larger sample are needed to detect a rate change by both methods. Our findings highlight the importance of enlarging the monitored population and correct case classification in birth defects surveillance.

Abnormalities, Drug-Induced↗
PubMed1998

Enantiomers of thalidomide: blood distribution and the influence of serum albumin on chiral inversion and hydrolysis.

The aim of this investigation was to elucidate the distribution and reactions of the enantiomers of thalidomide at their main site of biotransformation in vivo, i.e., in human blood. Plasma protein binding, erythrocyte: plasma distribution, and the kinetics of chiral inversion and degradation in buffer, plasma, and solutions of human serum albumin (HSA) were studied by means of a stereospecific HPLC assay. The enantiomers of thalidomide were not extensively bound to blood or plasma components. The geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide. The corresponding geometric mean blood:plasma concentration ratios were 0.86 and 0.95 (at a haematocrit of 0.37) and erythrocyte:plasma distributions were 0.58 and 0.87. The rates of inversion and hydrolysis of the enantiomers increased with pH over the range 7.0-7.5. HSA, and to a lesser extent human plasma, catalysed the chiral inversion, but not the degradation, of (+)-(R)- and (-)-(S)-thalidomide. The addition of capric acid or preincubation of HSA with acetylsalicylic acid or physostigmine impaired the catalysis to varying extents. Correction for distribution in blood enhances previously observed differences between the pharmacokinetics of the enantiomers in vivo. The findings also support the notion that chiral inversion in vivo takes place mainly in the circulation and in albumin-rich extravascular spaces while hydrolysis occurs more uniformly in the body. In addition, the chiral inversion and hydrolysis of thalidomide apparently occur by several different mechanisms.

Blood Proteins↗
PubMed2006

Efficacy of prophylactic warfarin for prevention of thalidomide-related deep venous thrombosis.

BACKGROUND: Deep venous thrombosis (DVT) is a common complication of thalidomide treatment. There is little information to guide clinicians in selecting effective preventive treatments and physician practice varies. We sought to determine whether prophylactic anticoagulation with warfarin prevents DVT related to thalidomide treatment. METHODS: We reviewed the records of 131 patients receiving thalidomide for a variety of indications. Fifty-five patients were prescribed warfarin with the intent of preventing DVT. Thirty-seven patients received warfarin at a dose of 1-2 mg per day (low dose) and 18 received a dose intended to raise the INR to 2-3 (high dose). RESULTS: Twenty-one of the 131 patients developed venous thrombosis during thalidomide treatment. Eighteen of the 76 patients (23.7%) who were not prescribed prophylactic anticoagulation developed DVT compared to 3 of the 55 patients (5.5%) who were prescribed any dose of prophylactic warfarin (P = 0.010). Only 1 of the 37 patients who received low-dose warfarin developed DVT (P = 0.011). Bleeding complications occurred in 4 patients, all of whom were receiving high-dose warfarin. CONCLUSION: Prophylactic anticoagulation with warfarin reduces the risk of thrombosis during thalidomide treatment. Low-dose warfarin may be as effective as higher dose treatment and may result in fewer bleeding complications.

Adult↗
PubMed2005

Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma.

BACKGROUND: The hypervascular nature of hepatocellular carcinoma (HCC) is well characterized. Recent data have suggested that thalidomide possesses antiangiogenic and immunomodulatory activity. Therefore, the authors initiated a study to assess the efficacy and toxicity of thalidomide in patients with advanced HCC as primary and secondary endpoints, respectively. METHODS: Inclusion criteria were unresectable HCC with bidimentionally measurable disease, age > or = 18 years, Eastern Cooperative Oncology Group performance status < or = 2, and adequate organ function. Thalidomide was administered at a starting dose of 200 mg per day in a 100-mg-per-week dose escalation regimen, up to the maximum tolerated dose or to 800 mg per day. Toxicity was monitored according to the National Cancer Institute Common Toxicity Criteria. RESULTS: Twenty-six of 27 patients were eligible and assessable for toxicity and response. A median daily dose of 300 mg was achieved. One patient experienced near-complete recovery of alpha-fetoprotein levels and a partial radiographic response on computed tomography. Two patients had stable disease during the 16-week study period. The median duration of progression-free survival was 42 days. The overall median survival was 123 days. Fatigue and somnolence were the most common side effects, occurring in 81% and 62% of patients, respectively. No Grade 4 hematologic toxicity was observed. Three patients experienced Grade 4 hepatic toxicity (namely, hyperbilirubinemia). CONCLUSIONS: With gradual dose escalation, thalidomide was tolerated in most patients with advanced HCC. However, treatment with thalidomide alone was associated with only a modest response in the treatment of HCC.

Adult↗
PubMed2005

Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial.

BACKGROUND: The treatment of patients with hepatocellular carcinoma (HCC) presents a major challenge, because associated cirrhosis limits the choice of chemotherapeutic agents. However, the abundant vascularity of HCC presents an attractive target for antiangiogenic therapy that potentially may be tolerated by cirrhotic patients. The current study was conducted to assess the antitumor activity, treatment tolerance, treatment-related toxicity, and patient survival after the administration of thalidomide in a Phase II trial. METHODS: Thirty-seven HCC patients were accrued between March, 1999, and March, 2000. Initially, the dose of oral thalidomide was escalated from 400 mg per day during the first week to 1000 mg per day by the fifth week, delivering one-third of the dose in the morning and the remaining two-thirds of the dose in the evening prior to bedtime. Changes in the daily drug administration schedule were allowed based on tolerance. Response was assessed at 8-week intervals. RESULTS: Thirty-two of 37 registered patients were evaluable for response. One patient had a partial response (PR), 1 patient had a minor response (MR), 10 patients had stable disease (SD) (31%; 95% confidence interval [95%CI], 16-51%), and 20 patients) (61%; 95%CI, 42-78%) had disease progression. The most commonly encountered toxicity was somnolence, with Grade 3-4 somnolence (>or= 4 hours of sleep during normal waking hours) in 9 patients (35%) and Grade 2 somnolence ( 800 mg if it was delivered at bedtime. Grade 3-4 skin reactions were observed in 20% of patients, and exfoliative dermatitis was observed in 1 responding patient. The overall median survival was 6.8 months. CONCLUSIONS: With a 5% PR rate, a 5% MR rate, and a 31% SD rate, the results indicate that thalidomide mostly may offer HCC patients disease stabilization. It is possible that, at a different dosage, or combined with other chemotherapy agents, or with the use of a different thalidomide analogue, longer patient survival may be achieved. However, in view of the significant neurologic toxicity encountered among these commonly cirrhotic HCC patients, thalidomide monotherapy at the high doses studied cannot be recommended for the treatment of HCC.

Adult↗
PubMed1996

Thalidomide inhibits tumor necrosis factor alpha, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal-hypertensive rats.

A hyperdynamic circulatory state frequently is observed in portal hypertension with liver failure or extensive portal-systemic shunting. Tumor necrosis factor alpha (TNF) causes marked hypotension in mammals by inducing nitric oxide synthesis and has been shown to play a role in the development of the hemodynamic changes observed in portal hypertension. Thalidomide selectively inhibits TNF production by enhancing messenger RNA degradation. We investigated the systemic and portal hemodynamic effects of thalidomide in a prehepatic model of portal hypertension and evaluated whether suppressing TNF synthesis decreases NO production. Portal hypertension was induced by partial ligation of the portal vein (PVL). Animals received thalidomide (T) (50 mg/kg/d) + water or water alone (W), orally, daily for 2 days before and 13 days after PVL operation, at which time hemodynamic studies were performed and TNF plasma levels were obtained. Sham-operated animals were studied identically. In an additional group of PVL animals, 24-hour urinary excretion of NO2- and NO3- was measured during treatment. PVL animals receiving T presented with a significantly higher mean arterial pressure and systemic vascular resistance and significantly lower portal pressure, TNF plasma levels, and 24-hour urinary excretion of NO2- and NO3-, in comparison with rats receiving W. A significant correlation (r = -0.61) was observed between TNF plasma levels and mean arterial pressure among PVL animals. Thalidomide did not have any significant effects on sham rats. Thalidomide inhibits TNF synthesis and reduces NO production, blunts the development of the hyperdynamic circulation, and decreases portal pressure in PVL-operated rats.

Animals↗
PubMed1992

Improvements in solubility and stability of thalidomide upon complexation with hydroxypropyl-beta-cyclodextrin.

Thalidomide is in clinical use for the treatment of graft-versus-host disease in leukemia patients after bone marrow transplant. Low levels of the drug in plasma after oral administration have made an intravenous thalidomide formulation desirable. Thalidomide, however, is sparingly soluble in aqueous solution (50 micrograms/mL) and unstable. Complexation with hydroxypropyl-beta-cyclodextrin has significantly improved the aqueous solubility and stability of thalidomide. Results obtained with HPLC and 1H NMR spectrometry have demonstrated that the solubility is increased to 1.7 mg/mL and the half-life of a diluted solution is extended from 2.1 to 4.1 h. Hence, an intravenous thalidomide-hydroxypropyl- beta-cyclodextrin solution has the potential to significantly improve current therapy for graft-versus-host disease by providing sustained high levels of drug in the plasma.

Cyclodextrins↗
PubMed2001

Thalidomide neuropathy in patients treated for metastatic prostate cancer.

We prospectively evaluated thalidomide-induced neuropathy using electrodiagnostic studies. Sixty-seven men with metastatic androgen-independent prostate cancer in an open-label trial of oral thalidomide underwent neurologic examinations and nerve conduction studies (NCS) prior to and at 3-month intervals during treatment. NCS included recording of sensory nerve action potentials (SNAPs) from median, radial, ulnar, and sural nerves. SNAP amplitudes for each nerve were expressed as the percentage of its baseline, and the mean of the four was termed the SNAP index. A 40% decline in the SNAP index was considered clinically significant. Thalidomide was discontinued in 55 patients for lack of therapeutic response. Of 67 patients initially enrolled, 24 remained on thalidomide for 3 months, 8 remained at 6 months, and 3 remained at 9 months. Six patients developed neuropathy. Clinical symptoms and a decline in the SNAP index occurred concurrently. Older age and cumulative dose were possible contributing factors. Neuropathy may thus be a common complication of thalidomide in older patients. The SNAP index can be used to monitor peripheral neuropathy, but not for early detection.

Action Potentials↗
PubMed1990

Thalidomide induced alteration in secondary structure of rat embryonic DNA in vivo.

Teratogenicity of thalidomide was demonstrated in Wistar rats following a single maternal intravenous injection during the embryonic organogenetic period. When compared to day 13 embryonic DNA isolated from untreated control mothers, differences were observed in the mean wet weights of day 13 embryos from rats treated with thalidomide during days 10 or 11 of gestation, and significantly less amounts of embryonic DNA were recovered from mothers similarly treated on days 10 or 12 of their respective gestation periods. Rat embryonic DNA may be separated into two fractions by stepwise elution from benzoylated DEAE-cellulose (BD-cellulose) columns with 1.0 M NaCl (SE-DNA) and 1.8% (w/v) caffeine (CE-DNA) solutions, respectively. Other studies using bacterial, yeast, and rat liver DNA suggested that the first fraction contains native DNA, whereas the second may exhibit some degree of single-stranded character. Similar reproducible chromatographic profiles were obtained using a novel "batch method" developed for general application. Rat embryonic DNA was monitored by labelling in vivo with an i.p. injection of [methyl-3H]-thymidine (3H-TdR) during days 5, 6, and 7 of the gestation period. All samples were analysed on day 13 of gestation. A simple increase in percentage of caffeine-eluted DNA was not detected in thalidomide treated samples; however, diversity of percent (%) CE-DNA within litter was noted. Briefly, the percent CE-DNA values for embryos in one litter were ranked and arbitrarily grouped in classes with limits of mean +/- 1 SD, mean +/- 2 SD, and so on to generate a characteristic profile of percent CE-DNA distribution. The number of embryos within the range of each SD unit was expressed as a percentage of each litter. A plot of the ranges of percent CE-DNA versus percentage of each litter was used to illustrate the distribution profile of the particular litter and to be used for comparison between samples from untreated control and thalidomide and/or dimethylformamide (DMF) treated DNA. Treatment of day 12 mothers with thalidomide produced a majority of embryos having percent CE-DNA values similar to those of untreated controls with the exception of the inclusion of a second population of embryos with much higher percent CE-DNA values than those of the untreated controls. Similar treatment of day 11 animals produced a majority of embryos still having percent CE-DNA values similar to those of untreated controls and also having a second group of embryos with a lower percent CE-DNA values than those of untreated controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

The effect of thalidomide and supidimide on endotoxin-induced uveitis in rats.

BACKGROUND: Endotoxin-induced uveitis (EIU) is an animal model of ocular inflammation, produced by footpad injection of endotoxin (lipopolysaccharide, LPS) to mimic the human disease of acute anterior uveitis, that is useful for testing new anti-inflammatory therapy. The purpose of this study was to test the anti-inflammatory effect on EIU of thalidomide and one of its derivatives, supidimide. METHODS: EIU was produced in rats by hind foot-pad injection of LPS (100 micrograms/animal). Animals were killed 20 h after LPS injection. Inflammation was evaluated by anterior chamber determination of proteins and cells. RESULTS: A dosage of 400 mg/kg per day of thalidomide was efficient in reducing inflammation whether given in three doses (at -24 h, -4 h and +4 h relative to LPS challenge = THAL-1; p < 0.001 for proteins and cells), in two doses (-4 h and +4 h = THAL-2; p < 0.001 for proteins, p < or = 0.012 for cells) or in one dose (at +4 h = late THAL; p < 0.001 for proteins, p < or = 0.02 for cells). A dosage of 300 mg/kg per day of thalidomide was still efficient (p < or = 0.023 for proteins, p < or = 0.06 for cells), but 150 mg/kg per day had no effect on inflammation. Supidimide (400 mg/kg per day) had some anti-inflammatory effect (p < or = 0.053 for proteins, p < or = 0.06 for cells). CONCLUSION: High-dose thalidomide had a potent anti-inflammatory effect in EIU, but lower doses were not sufficient to reduce inflammation. At similar high doses, supidimide had some effect on EIU but was less effective than thalidomide.

Acute Disease↗