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PubMed1999

Effect of thalidomide, octreotide, and prednisolone on the migration and proliferation of RPE cells in vitro.

PURPOSE: The retinal pigment epithelium (RPE) is involved in the pathogenesis of age-related macular degeneration. The purpose of this study was to assess the effect of thalidomide, octreotide, and prednisolone on the proliferation and migration of bovine RPE cells in vitro. METHODS: The migration assay was performed in double-chamber-wells separated by a membrane filter with 8 microm pores. Cells were allowed to migrate vertically for 7 hr, afterwards the cells on both filtersides were fixed, stained, and the migrated cells were counted. To examine RPE proliferation, bovine RPE cells were seeded subconfluently followed by an incubation with octreotide, thalidomide or prednisolone in a concentration gradient for 24 hr. Stimulation or inhibition of DNA synthesis was measured by [(3)H]-thymidine incorporation. Statistical analysis was performed with the paired student's t-test. RESULTS: Statistically significant (p < 0.05) inhibition of RPE cell proliferation was measured for thalidomide at a concentration of 10-50 microg/ml, for octreotide at a concentration of 5 x 10(-4) and 5 x 10(-5) M, and for prednisolone at a concentration of 250 and 500 microg/ml as compared to the negative control. RPE cell migration was significantly (p < 0.05) inhibited by thalidomide at a concentration of 10 microg/ml, by octreotide at a concentration of 5 x 10(-5) M, and also by prednisolone at a concentration of 500 microg/ml as compared to the negative control. CONCLUSIONS: Although the main effect of thalidomide, octreotide, and prednisolone when treating patients with choroidal neovascular membranes is probably related to the inhibition of angiogenesis it should be kept in mind that these substances may additionally inhibit RPE proliferation and migration.

Animals↗
PubMedDate not supplied

Antipruritic action of thalidomide.

The effect of thalidomide on itch was studied in 11 patients with chronic pruritus from psoriasis, eczema, nodular prurigo, senile pruritus and primary biliary cirrhosis. Itch, assessed subjectively by the patients on a 10 cm line and measured objectively as nocturnal scratch movement, was decreased by thalidomide 200 mg on the 2 nights it was given. There was no improvement in the underlying disorders and it is concluded that thalidomide is a primary antipruritic agent. The patients all became drowsy and it seems likely that, as with most other antipruritic agents, the antipruritic action of thalidomide results from a central depressant effect. The primary antipruritic effect of thalidomide should now be assessed therapeutically.

Adult↗
PubMed2002

Thalidomide in low doses is effective for the treatment of resistant or relapsed multiple myeloma and for plasma cell leukaemia.

Thalidomide is an effective treatment for relapsed multiple myeloma (MM), but is associated with a significant side effect profile at higher doses. In a recent study, only half of the enrolled patients were able to tolerate the maximum dose of 800 mg/day [Singhal, S., et al. (1999) "Antitumor activity of thalidomide in refractory multiple myeloma", New Engl. J. Med. 341, 1565-1571]. Moreover, the dose-response relationship has not been defined. We report our use of low dose thalidomide in a small cohort of 12 patients-eight with relapsed or refractory MM and four with plasma cell leukaemia (PCL). Five of the 12 (42%) patients had a partial response, showing a median fall in their PP/BJP of 80% (63-90%) at a median dose of 175 mg (100-300 mg) with negligible side effects. Three of four patients with PCL showed an impressive response to treatment with thalidomide as a single agent. No patient who failed to show any evidence of response at low dose (<150 mg/day) responded to higher doses. In this study, thalidomide induces a similar rate of response at a lower and better tolerated dose than previously reported and produced "best ever" responses in patients with resistant PCL.

Adult↗
PubMed2004

Possible multiple myeloma dedifferentiation following thalidomide therapy: a report of four cases.

Thalidomide has been shown to be effective in approximately 30% of patients with refractory or advanced multiple myeloma (MM). Here we report on 4 cases of patients treated with thalidomide for refractory MM showing dedifferentiation of the neoplasm. In these cases thalidomide treatment despite reduction of M-component-was followed by disease progression and a very poor clinical outcome which was paralleled by bone marrow plasmacytosis showing marked signs of dedifferentiation, inducing us to speculate on a potential role of thalidomide on dedifferentiation of myeloma cells. In our opinion, a possible dedifferentiation of MM should therefore be taken into account in MM patients treated with thalidomide when clinical course deteriorates despite reduction of M-component.

Aged↗
PubMedDate not supplied

Preparation and in vitro analysis of microcapsule thalidomide formulation for targeted suppression of TNF-alpha.

Recent studies have implicated the cytokine tumor necrosis factor-alpha (TNF-alpha) in the inflammation associated with Crohn's disease (CD). Thalidomide has been shown to decrease this inflammation by the suppression of TNF-alpha secretion. However, side effects associated with thalidomide have precluded its widespread usage. In the present study we investigated the efficacy of a "targeted delivery approach" for thalidomide at the site of inflammation. We observed that alginate-poly-l-lysine-alginate (APA) polymer-based microcapsule formulations that encapsulate thalidomide could be designed. These capsules could be delivered at target sites where they almost entirely suppress TNF-alpha secretion in lipopolysaccharide activated RAW 264.7 macrophage cells in vitro. These findings indicate that targeted delivery of thalidomide using APA capsules could facilitate its usage in reducing the inflammation associated with chronic conditions such as Crohn's disease and ulcerative colitis.

Alginates↗
PubMed2002

Thalidomide given intraperitoneally reduces the number of postoperative adhesions after large bowel resection in rabbits.

OBJECTIVE: To investigate the effect of thalidomide given intraperitoneally on the formation of adhesions after colonic resection in rabbits. DESIGN: Controlled, randomised prospective study. SETTING: University hospital, Germany. ANIMALS: 40 female New Zealand White rabbits. INTERVENTIONS: After an end-to-end colonic anastomosis the animals were given thalidomide 200 mg/kg in 1% carboxymethylcellulose intraperitoneally or carboxymethylcellulose alone (n = 20 in each group). OUTCOME MEASURES: The adhesion score according to Tyrell on day 3 (n = 20) and day 7 (n = 20) postoperatively, weight, behaviour, and white cell count (WCC). RESULTS: There was no difference in behaviour or weight. On the third postoperative day WCCs and on the seventh postoperative day WCCs and adhesion scores, were lower in the thalidomide group (p < 0.01). CONCLUSION: The number of postoperative adhesions was reduced in the group given thalidomide intraperitoneally. Our results suggest that thalidomide may be helpful in the prevention of postoperative adhesions.

Angiogenesis Inhibitors↗
PubMed2000

Effect of thalidomide on chemokine production by human microglia.

Thalidomide, a psychoactive drug that readily crosses the blood-brain barrier, has been shown to possess immunomodulatory attributes, including the inhibition of cytokine production by monocytes and microglia. In this study, we investigated the effect of thalidomide on chemokine production by human microglial cells. Microglial cells were stimulated with lipopolysaccharide, a key cell-wall component of gram-negative bacteria responsible for meningitis, and production of chemokines (regulated upon activation normally T cell expressed and secreted [RANTES], monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1beta, and interleukin [IL]-8) was examined by ELISA. Thalidomide treatment was found to cause potent and selective inhibition of IL-8 production in a dose-responsive manner. This inhibition was associated with decreased intracellular IL-8 staining as well as reduced transcription of IL-8 mRNA. In addition, thalidomide treatment of lipopolysaccharide-stimulated microglia inhibited the activation of protein NF-kappaB, a transcription factor known to be important for IL-8 production. These results suggest thalidomide could have a therapeutic role in acute bacterial meningitis through inhibition of IL-8-mediated neutrophil chemotaxis.

Cells, Cultured↗
PubMed2001

The immunomodulatory effects of thalidomide on human immunodeficiency virus-infected children.

The safety and immune effects of low-dose thalidomide treatment (3 mg/kg/day for 28 days) were evaluated in a study involving 8 South African human immunodeficiency virus (HIV)-infected children. The children were 7-69 months old and in disease stages A1-C3. Thalidomide therapy did not affect virus load, even though none of the children was receiving antiretroviral therapy. Thalidomide stimulated CD8+ T cells in peripheral blood, which increased expression of the activation markers CD38 and human leukocyte antigen DR and of the memory cell marker CD45RO. The frequency of HIV gag-specific CD8+ T cells in peripheral blood increased in 3 of 4 children who were evaluated during treatment with thalidomide. Clinical adverse events were mild. In this study, thalidomide was found to be safe and well tolerated and caused significant immunomodulation at a low dose. This is the first report describing use of an oral drug that may enhance HIV-specific CD8+ T cell function in HIV-infected children.

Anti-HIV Agents↗
PubMed2002

Safety, tolerability, and pharmacokinetic effects of thalidomide in patients infected with human immunodeficiency virus: AIDS Clinical Trials Group 267.

Thalidomide is used to treat human immunodeficiency virus (HIV)-associated conditions, including aphthous ulcers and wasting syndrome. The safety, tolerability, and pharmacokinetics of a formulation of thalidomide with improved bioavailability in HIV-infected persons was examined in a placebo-controlled, dose-escalating phase 1 study. Subjects with CD4 cell counts of 200-500 cells/mm(3) were enrolled and randomized 3:1 in groups of 12 to receive 50, 100, or 150 mg of thalidomide or matching placebo. Two subjects who received 150 mg of drug and 2 subjects assigned placebo experienced dose-limiting toxicity. Concentrations of thalidomide in the blood increased with escalating dose, but the time to maximum concentration and clearance did not differ across dose cohorts. Previous suggestions of autoinduction of drug metabolism were not confirmed by this study. At the doses studied, thalidomide was tolerated well and had linear pharmacokinetics.

Adult↗
PubMed2005

Effective treatment of erythema nodosum leprosum with thalidomide is associated with immune stimulation.

The immunomodulatory drug thalidomide is the treatment of choice for erythema nodosum leprosum (ENL), an inflammatory cutaneous and systemic complication of multibacillary leprosy. To elucidate the mechanism of action of thalidomide in this syndrome, we prospectively investigated 20 patients with ENL who were treated with thalidomide for 21 days. All patients responded to treatment, with the majority of them having complete resolution of cutaneous lesions within 7 days. This response was associated with a marked but transient increase in ex vivo mitogen-induced expression of interleukin (IL)-2 and interferon- gamma by CD4(+) and CD8(+) T cells that was observed on treatment day 7, but these returned to pretreatment levels by day 21. Plasma tumor necrosis factor- alpha levels were not high at baseline, and they increased modestly during treatment. Plasma levels of IL-12 increased steadily during thalidomide treatment. Hence, the therapeutic effect of thalidomide in ENL appears to be associated with transient immune stimulation, which suggests that the drug may promote an active immunoregulatory response.

Adolescent↗
PubMed2000

Thalidomide for the treatment of AIDS-associated wasting.

A double-blind, placebo-controlled trial of efficacy and safety of thalidomide in AIDS-associated wasting was carried out. Ninety-nine of 103 male patients had at least one on-study measurement (intent-to-treat [ITT] cohort). Patients were randomized to thalidomide at 100 mg/day (T100) or 200 mg/day (T200), or placebo for 8 weeks. By ITT analysis, the mean change in body weight of the placebo, T100, and T200 treatment groups was 0.3 kg (0.4%), 2.0 kg (3.0%), and 0.9 kg (1.4%), respectively (p = 0.021 for T100 versus placebo; p = 0.53 for T200 versus placebo). Of the 64 patients who completed the 8 weeks of study treatment, significant weight gain was observed in both the T100 group (2.2 kg, [33%]; p = 0.008 versus placebo) and the T200 group (1.5 kg [2.5%]; p = 0.019 versus placebo). Approximately half the weight gain was fat-free mass (bioimpedance analysis). Patients in the T100 or T200 groups had no significant change in CD4+ cell counts, neutrophil counts, or TNF-alpha levels, compared with placebo. HIV viral load measured as log10 copies/ml decreased by a median of 0.07 in the placebo group, and increased by a median of 0.29 (T100 group) and 0.23 (T200 group) (p = 0.024 andp = 0.018 versus placebo, respectively). Thalidomide therapy was associated with mild to moderate rashes and fevers, but not peripheral neuropathy. Although the anabolic benefits of high-dose thalidomide are limited by drug intolerance, 8 weeks of low-dose thalidomide results in significant weight gain in patients with AIDS-associated wasting.

Adult↗
PubMed1999

Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects.

Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor necrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disorders. The pharmacokinetics and hemodynamic effects of two single oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized, two-period crossover design, in a group of asymptomatic, male HIV-seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one-compartment model with first-order absorption and elimination processes. The drug was rapidly absorbed, with a mean absorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.33-3.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean Cmax values were 1.15+/-0.24 microg/ml (100 mg) and 1.92+/-0.47 microg/ml (200 mg; p<0.001), which were achieved (Tmax) at 2.5+/-1.5 h and 3.3+/-1.4 hr, respectively. Plasma concentrations of thalidomide declined thereafter, in a log-linear manner, with elimination half-lives of 4.6+/-1.2 hr (100 mg) and 5.3+/-2.2 hr (200 mg). The apparent volumes of distribution (Vdss/F) were 69.9+/-15.6 liters (100 mg) and 82.7+/-34.9 liters (200 mg) while total body clearances (Cl/F) were 10.4+/-2.1 and 10.8+/-1.7 liters/hr, respectively. Significant dose-dependent decreases in supine systolic and diastolic blood pressures were seen for up to 2 hr postdosing; somnolence, headache, dizziness, and confusion were also reported more frequently at the higher dose of thalidomide.

Administration, Oral↗
PubMed2003

IFN-alpha2b and thalidomide synergistically inhibit tumor-induced angiogenesis.

Angiogenesis is an absolute requirement for tumor growth and metastasis. The purpose of this study was to evaluate the antiangiogenic activity of interferon-alpha2b (IFN-alpha2b) and thalidomide, as single agents and in combination. The murine dermis model was used to assess tumor-induced angiogenesis in nude mice. Human ACHN (renal), NIH-OVCAR-3 (ovarian), LNCaP (prostate), and SK-Mel-1 (melanoma) tumor cells were inoculated intradermally into the flanks of nude mice. IFN-alpha2b and thalidomide, administered daily, were effective inhibitors of angiogenesis induced by all four tumor types. The combination of IFN-alpha2b and thalidomide caused a synergistic decrease in mean vessel count in tumors that were resistant to the antiproliferative effects of IFN-alpha2b and thalidomide in vitro. This enhanced suppression of angiogenesis translated into synergistic antitumor activity in a xenograft model. Pegylated IFN-alpha (PEG-IFN-alpha2b) (10(6) U) administered once in 10 days was as effective as daily IFN-alpha2b treatment (10(6) U x 10 days). IFN-alpha2b and thalidomide have potentiated antiangiogenic activity when used in combination. A single dose of PEG-IFN-alpha2b (10(6) U) was as effective at suppressing vessel growth as an equivalent dose of IFN-alpha2b given daily for 10 days.

Angiogenesis Inhibitors↗
PubMed2004

A novel hypothesis for thalidomide-induced limb teratogenesis: redox misregulation of the NF-kappaB pathway.

Several hypotheses have been proposed to explain the mechanisms of thalidomide teratogenesis, although none adequately accounts for the observed malformations and explains the basis for species specificity. Recent observations that thalidomide increases the production of free radicals and elicits oxidative stress, coupled with new insights into the redox regulation of nuclear transcription factors, lead to the suggestion that thalidomide may act through redox misregulation of the limb outgrowth pathways. Oxidative stress, as marked by glutathione depletion/oxidation and a shift in intracellular redox potential toward the positive, occurs preferentially in limbs of thalidomide-sensitive rabbits, but not in resistant rats. DNA binding of nuclear factor kappa-B (NF-kappaB), a redox-sensitive transcription factor and key regulator of limb outgrowth, was shown to be significantly attenuated in rabbit limb cells and could be restored following the addition of a free radical spin-trapping agent, phenyl N-tert-butyl nitrone. The inability of NF-kappaB to bind to its DNA promoter results in the failure of limb cells to express fibroblast growth factor (FGF)-10 and twist in the limb progress zone (PZ) mesenchyme, which in turn attenuates expression of FGF-8 in the apical ectodermal ridge (AER). Failure to establish an FGF-10/FGF-8 feedback loop between the PZ and AER results in the truncation of limb outgrowth. We hypothesize that species-selective alterations in redox microenvironment caused by free radical production from thalidomide results in attenuation of the NF-kappaB-mediated gene expression that is responsible for limb outgrowth.

Animals↗
PubMed1997

A double-blind placebo-controlled phase II trial of thalidomide in asymptomatic HIV-positive patients: clinical tolerance and effect on activation markers and cytokines.

A randomized double-blind, placebo-controlled study was performed to determine the safety, efficacy, and effect of thalidomide on a variety of immunological and biochemical parameters in asymptomatic human immunodeficiency virus (HIV)-positive patients. Nineteen male patients with elevated markers of immune activation and CD4 cell counts above 400/mm3 were randomized to either placebo or thalidomide at 100 mg/day for 24 weeks. However, only 3 (of 10) patients receiving thalidomide completed all 24 weeks compared to 6 (of 9) patients receiving placebo. This was mainly due to fatigue (somnolence is a recognized side effect), although this was also seen to a lesser extent in the placebo group and so may not be drug attributable. No significant changes in CD4/CD8 count, activation markers, TNF-alpha, or TNFR1 were observed. However, a nonsignificant trend toward inhibition of mitogen-induced TNF-alpha production was observed in the thalidomide arm. The lack of systemic effect and the lower tolerance of thalidomide (at this dose) in asymptomatic patients highlights the need for pharmacokinetic analysis to address possible absorption problems and the need for more potent and less toxic TNF-alpha inhibitors to be developed for use in this type of study.

Adult↗
PubMed1997

A prospective trial of thalidomide for the treatment of HIV-associated idiopathic esophageal ulcers.

Thalidomide appears to be highly effective for oropharyngeal apthous ulcers in HIV-infected patients. However, there are limited data regarding the use of this drug for the treatment of HIV-associated idiopathic esophageal ulcer(s) (IEU). Twelve HIV-infected patients with esophageal symptoms and IEU as defined by previously proposed criteria were studied prospectively. Two of these patients had failed oral corticosteroid treatment, and two others had a previous history of IEU. Patients were treated with thalidomide (200 mg/day orally) for 28 days in an open label fashion. Clinical evaluation was performed weekly with endoscopic reexamination performed at the completion of treatment. After therapy, patients were followed clinically with endoscopy recommended for recurrent esophageal symptoms. Of the 12 treated patients, 11 (92%) had a complete symptomatic response; endoscopy in 11 patients at the completion of treatment showed 9 with complete ulcer healing, 1 partially healed, and 1 with no response. All responders were asymptomatic by day 28. The partial responder received an additional 1 month of thalidomide at 300 mg/day, resulting in complete endoscopic healing. The patient failing therapy received prednisone, but died prior to completing this therapy. On follow-up to 20 months, six patients have died with no recurrence of IEU. Three patients had relapse of IEU, two of whom had a prior history of multiple recurrences of IEU; both of these patients relapsed within 2 months of completing thalidomide treatment. The drug was well tolerated without significant side effects. Thalidomide appears to be an effective and well-tolerated alternative to prednisone for the treatment of IEU.

Adult↗
PubMed2002

Consolidation therapy of multiple myeloma with thalidomide-dexamethasone after intensive chemotherapy.

BACKGROUND: After myeloablative therapy for multiple myeloma, progression-free survival is shorter for disease in partial remission rather than complete remission. In an attempt to induce more frequent complete remission, we assessed thalidomide-dexamethasone in patients with stable partial remission after intensive therapy. PATIENTS AND METHODS: Twenty-one patients with multiple myeloma were identified with disease in stable partial remission after prior intensive therapy. Thalidomide-dexamethasone was given within 15 months after intensive therapy provided myeloma protein production had been reduced by >75% to a constant level for at least 4 months. Thalidomide was begun at a dose of 100 mg each evening, with increments of 50 mg every 7 days to a maximum of 300 mg. Dexamethasone was given concurrently in a dose of 20 mg/m(2) each morning for 4 days on days 1-4, 9-12 and 17-20, with resumption on day 35. The combination was continued for at least 3 months and patients with marked reduction of myeloma were maintained on thalidomide alone until disease progression. RESULTS: Marked further reduction of myeloma by at least 90% occurred in 12 patients (57%), including four (19%) with disease converted to complete remission. Disease has progressed in six of 21 patients, whose median total remission was 22 months. Common side effects of constipation, fatigue, paresthesias and dry skin were mild, dose-related and reversible. CONCLUSIONS: The combination of thalidomide-dexamethasone reduced tumor mass markedly in 57% of patients with stable, residual disease after myeloablative therapy. Such an effect may produce longer disease-free survival and/or preserve tumor sensitivity to later retreatment with previously effective drugs.

Adult↗
PubMed2004

Thalidomide in cancer medicine.

Thalidomide, an oral agent with antiangiogenic and immunomodulatory properties, is being investigated extensively in the management of advanced cancer. Multiple studies with large numbers of patients have confirmed that this drug has significant activity in multiple myeloma. Some patients with myelofibrosis or myeodysplatic syndromes may reduce their need for transfusions after thalidomide treatment. The activity of thalidomide in solid tumors is less prominent. Studies in Kaposi's sarcoma, malignant melanoma, renal cell carcinoma and prostate cancer appear more promising especially when thalidomide is combined with biological agents or with chemotherapy. Limited activity was demonstrated in patients with glioma, while thalidomide appears to be inactive in patients with head and neck cancer, breast or ovarian cancer.

Angiogenesis Inhibitors↗