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PubMed2000

Thalidomide inhibits angiogenesis in embryoid bodies by the generation of hydroxyl radicals.

Thalidomide is a teratogen with anti-angiogenic properties and causes stunted limb growth (dysmelia) during human embryogenesis. The molecular mechanisms of thalidomide action in embryopathy are currently unknown. Using the endothelial-specific antigen platelet endothelial cell adhesion molecule-1 and confocal laser scanning microscopy we have demonstrated that thalidomide exerts anti-angiogenic effects on the development of capillary structures in embryoid bodies differentiated from murine embryonic stem cells. Consequently, in thalidomide-treated embryoid bodies the diffusion properties of the tissue were deteriorated. Thalidomide raised reactive oxygen species (ROS), as revealed using 2'7'-dichlorodihydrofluorescein diacetate (H(2)DCF-DA) as an indicator. A comparable ROS generation was achieved with the thalidomide hydrolysis product phthaloyl glutamic acid (PGA), but not with phthalimide (PI), the major component of thalidomide. ROS formation by thalidomide was inhibited by the hydroxyl radical scavengers mannitol and 2-mercaptoethanol. After coadministration of either 2-mercaptoethanol or mannitol with thalidomide the anti-angiogenic effects of thalidomide were abolished and the diffusion properties of the tissue were restored to the control values. In summary, our data suggest that thalidomide exerts its anti-angiogenic properties via the generation of toxic hydroxyl radicals, which impair vasculogenesis and angiogenesis during embryoid body development.

Angiogenesis Inhibitors↗
PubMed1998

A double-blind study of the sedative effects of the thalidomide enantiomers in humans.

This study investigated the sedative effects of the enantiomers of thalidomide in humans. Since the enantiomers undergo chiral inversion in vivo this entailed application of suitable statistical methodology to distinguish the effects of each enantiomer in the presence of the other one. Six healthy male volunteers received single oral doses of (+)-(R)-thalidomide, (-)-(S)-thalidomide or racemic thalidomide in a double-blind study, and the results of this study were compared with those of a similar study where three subjects received (+)-(R)-thalidomide, (-)-(S)-thalidomide or placebo in a double-blind fashion. Blood samples for analysis of (+)-(R)-thalidomide and (-)-(S)-thalidomide were obtained. Prior to sampling it was noted whether the subject was awake or asleep, and his feelings of tiredness and heaviness were estimated using Borg scales. After blood sampling continuous reaction time was measured by a 10-min series of auditory signals. The concentration-effect relationships were analyzed by logistic regression techniques and Cox regression for the reaction time data. The (+)-(R)-thalidomide concentrations, but not the (-)-(S)-thalidomide concentrations, exhibited significant positive influences on all sedative effects studied (sleep, tiredness, and reaction times). In some of the analyses of reaction times the (-)-(S)-thalidomide concentrations had a significant effect in the opposite direction. The time course and intensity of sedative effect is thus influenced by which enantiomer is administered and by the kinetics of in vivo chiral inversion.

Adult↗
PubMed2004

Thalidomide effects in the post-transplantation setting in patients with multiple myeloma.

UNLABELLED: Thalidomide recently has been proven to have an impact on plasma cell dyscrasia through multiple mechanisms. Its effects on hematopoietic stem cells both in harvesting and in the immediate post-transplant setting are still unknown. We report on 12 cases (9 males and 3 females), median age 56 years old (range 41-65 years old) who underwent autologous peripheral stem cell transplantation for multiple myeloma and received thalidomide as maintenance therapy post-transplantation. Patients received various cytoreductive therapies prior to stem cell harvest. Eleven patients were in partial remission (PR) and one in complete remission (CR) on entry into the transplant phase of therapy. The median CD34+/kg harvested was 4.7 x 10(6) (range 1.9-55.4 x 10(6) CD34+/kg). All patients received intravenous melphalan 200 mg/m2 as their conditioning regimen. Six of twelve patients attained a CR post-transplant, and six a PR. Thalidomide was started after all patients engrafted post-transplant (absolute neutrophil count >0.5 x 10(9)/l and self-sustained platelet count >20 x 10(9)/l) and following satisfactory resolution of transplant toxicity including mucositis and diarrhea. Thalidomide was initiated at a median of 43 days post-transplant (range 23-138 days). The median leukocyte and platelet counts at the moment of thalidomide initiation were 5.8 x 10(9)/l (range 2.9-8.6 x 10(9)/l) and 196 x 10(9)/l (range 30-351 x 10(9)/l), respectively. Thalidomide was started at 100 mg daily, increasing 100 mg/day/month until reaching a dose of 400 mg/day. One patient failed to tolerate thalidomide due to CNS symptoms and stopped therapy at 12 days. Another patient stopped thalidomide therapy after 71 days, because of severe fatigue secondary to hypothyroidism. The most common adverse effects were constipation (5), rash (4), dry skin (3) and dizziness (3). No grade 3-4 adverse effects were documented. Neutropenia, previously reported as an adverse effect in this setting, was not seen to date in our cohort. All patients attained a CR or PR after transplant and thalidomide maintenance. We have had two relapses during a median follow-up of 68 weeks (range 42-172 weeks). CONCLUSION: Thalidomide appears to be a safe drug in the post-transplant setting, perhaps adding to the response achieved post-transplant without major toxicity. Longer follow up and future randomized trials will be needed to validate the role of thalidomide and its long-term effect when used as maintenance therapy in the post-transplant setting.

Aged↗
PubMed2004

The effect of thalidomide on non-small cell lung cancer (NSCLC) cell lines: possible involvement in the PPARgamma pathway.

Lung cancer is the leading cause of cancer-related death in developed countries. Non-small cell lung cancer (NSCLC) represents 80% of the total lung cancer cases and is comprised of adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma and large cell carcinoma (LCC) subtypes. The ability of LCC to metastasize earlier than the other forms of lung cancer suggests anti-angiogenic drugs as effective agents to combat this cancer. Thalidomide is an anti-angiogenic drug that has shown promise in multiple hematological diseases, and myeloma and other cancers. However, the molecular mechanism by which thalidomide exerts its effects is poorly understood. Therefore, we evaluated the effectiveness of thalidomide on NSCLC cell growth, and found that LCC cells were growth inhibited by 40-60%. This effect seemed specific to LCC cancer cells, since other forms of NSCLC were only mildly affected by thalidomide. At the molecular level, thalidomide increased peroxisome proliferator-activated receptor gamma (PPARgamma) protein dose-dependently, and peroxisome proliferator response element activity. Further, thalidomide treatment of LCC cells decreased nuclear factor kappa B activity in a dose-dependent fashion, increased apoptosis and decreased the expression of angiogenic proteins. In our mouse xenograft model of lung cancer, we found that intratumoral thalidomide caused a 64% decrease in tumor growth; moreover, tumors from the thalidomide-treated mice expressed higher PPARgamma, than tumors from control mice. This study shows the antitumor activity of thalidomide against LCC tumors and suggests a model in which thalidomide exerts its antitumor effects on LCC cells through the induction of PPARgamma and subsequent downstream signaling. To our knowledge, this is the first study to show a link between thalidomide and PPARgamma.

Angiogenesis Inhibitors↗
PubMed2004

Antitumor effects of thalidomide analogs in human prostate cancer xenografts implanted in immunodeficient mice.

PURPOSE: Thalidomide has demonstrated clinical activity in various malignancies including androgen-independent prostate cancer. The development of novel thalidomide analogs with better activity/toxicity profiles is an ongoing research effort. Our laboratory previously reported the in vitro antiangiogenic activity of the N-substituted thalidomide analog CPS11 and the tetrafluorinated analogs CPS45 and CPS49. The current study evaluated the therapeutic potential of these analogs in the treatment of prostate cancer in vivo. EXPERIMENTAL DESIGN: Severely combined immunodeficient mice bearing s.c. human prostate cancer (PC3 or 22Rv1) xenografts were treated with the analogs at their maximum tolerated doses. Tumors were then excised and processed for ELISA and CD31 immunostaining to determine the levels of various angiogenic factors and microvessel density (MVD), respectively. RESULTS: CPS11, CPS45, and CPS49 induced prominent and modest growth inhibition in PC3 and 22Rv1 tumors, respectively. Thalidomide had no effect on tumor growth in either xenograft. Vascular endothelial growth factor and basic fibroblast growth factor levels were not significantly altered by any of the thalidomide analogs or thalidomide in both PC3 and 22Rv1 tumors. CPS45, CPS49, and thalidomide significantly reduced PC3 tumor platelet-derived growth factor (PDGF)-AA levels by 58-82% (P < 0.05). Interestingly, treatment with the analogs and thalidomide resulted in differential down-regulation (>/=1.5-fold) of genes encoding PDGF and PDGF receptor isoforms as determined by DNA microarray analysis. Intratumoral MVD of 22Rv1 xenografts was significantly decreased by CPS45 and CPS49. CPS49 also reduced MVD in PC3 xenografts. CONCLUSIONS: Thalidomide analogs CPS11 and 49 are promising anti-cancer agents. PDGF signaling pathway may be a potential target for these thalidomide analogs. Detailed microarray and functional analyses are under way with the aim of elucidating the molecular mechanism(s) of action of these thalidomide analogs.

Animals↗
PubMed2003

Treatment of plasma cell dyscrasias with thalidomide and its derivatives.

PURPOSE: In 1999, investigators reported promising results of a phase II study of thalidomide in patients with resistant multiple myeloma (MM). Since then, various trials of thalidomide alone and in combination with other agents have been tested in patients with resistant and, more recently, untreated MM. In addition, preliminary results of phase I studies of the immunomodulatory derivatives (IMiDs) of thalidomide have been recently reported. DESIGN: We reviewed and report the results of clinical trials of thalidomide and the IMiDs, as well as the pharmacology, mechanism of action, and toxicity of these agents. RESULTS: Thalidomide has demonstrated significant activity in both resistant and previously untreated multiple myeloma. Combination therapy with dexamethasone increases response rate, even in patients previously resistant to both drugs given as single agents. More recent studies of thalidomide with dexamethasone in previously untreated patients are highly encouraging. The addition of chemotherapy to thalidomide and dexamethasone may further increase response rates, but its effect on patient survival has not been clarified. Preliminary results of trials of IMiD-3 indicate that this agent is active in resistant myeloma and has a toxicity profile different from that of thalidomide. CONCLUSION: Many studies have confirmed the activity of thalidomide in MM, as well as an improved response with dexamethasone. Newer thalidomide derivatives with reduced toxicity (neuropathy, teratogenicity) are also promising. Thalidomide with dexamethasone may now represent the treatment of choice for previously untreated patients. Further studies with these and other novel agents early in the course of myeloma may improve complete remission rates and frequency of long-term control.

Adjuvants, Immunologic↗
PubMed2000

Intravenous formulations of the enantiomers of thalidomide: pharmacokinetic and initial pharmacodynamic characterization in man.

Thalidomide, a racemate, is coming into clinical use as an immunomodulating and antiinflammatory drug. These effects may chiefly be exerted by S-thalidomide, but the enantiomers are interconverted in-vivo. Thalidomide is given orally, although parenteral administration would be desirable in some clinical situations. The aim of this study was to prepare solutions of the enantiomers of thalidomide for intravenous administration and to investigate their pharmacokinetics and sedative effects following infusion in man. Solubility and stability of the enantiomers in 5% glucose solution was investigated. After a dose-determination experiment in one subject, six healthy male volunteers received R- and S-thalidomide separately by 1-h infusions in a randomized double-blind cross-over study. Blood was sampled over 22h and sedative effects were recorded. Blood concentrations of the enantiomers were determined by stereospecific HPLC. A four-compartment model consisting of a two-compartment model for each enantiomer, with elimination from both compartments, connected by rate constants for chiral inversion was fitted to the concentration data, while the sedative effects were correlated with the blood concentrations of R- and S-thalidomide by means of logistic regression. The enantiomers of thalidomide were chemically stable in solution for at least a week at room temperature. The infusions were well tolerated. Sedation, which was the only observed effect, was related to the blood concentration of R-thalidomide. Inter-individual variation in the disposition of the enantiomers was modest (e.g. terminal half-lives ranged between 3.9 and 5.3h). Pharmacokinetic modelling predicted that varying the infusion time of a fixed dose of S-thalidomide between 10 min and 6h would have little influence on the maximal blood concentration of formed R-thalidomide. To our knowledge this is the first time that thalidomide has been administered intravenously.

Adult↗
PubMed2007

Enantioselectivity of thalidomide serum and tissue concentrations in a rat glioma model and effects of combination treatment with cisplatin and BCNU.

Thalidomide is currently under evaluation as an anti-angiogenic agent in cancer treatment, alone and in combination with cytotoxic agents. Thalidomide is a racemate with known pharmacologic and pharmacokinetic enantioselectivity. In a previous study with thalidomide combination chemotherapy, we found evidence of anti-tumour synergy. In this study, we examined whether the synergy involved altered pharmacokinetics of thalidomide enantiomers. Adult female F344 rats were implanted with 9L gliosarcoma tumours intracranially, subcutaneously (flank), or both. Effectiveness of oral thalidomide alone, and with intraperitoneal BCNU or cisplatin combination chemotherapy, was assessed after several weeks treatment. Presumed pseudo steady-state serum, tumour and other tissues, collected after treatment, were assayed for R- and S-thalidomide by chiral HPLC. Both serum and tissue concentrations of R-thalidomide were 40-50% greater than those of S-thalidomide. Co-administration of BCNU or cisplatin with thalidomide did not alter the concentration enantioselectivity. Poor correlation of concentration with subcutaneous anti-tumour effect was found for individual treatments, and with all treatments for intracranial tumours. The consistency of the enantiomer concentration ratios across treatments strongly suggests that the favourable antitumour outcomes from interactions between thalidomide and the cytotoxic agents BCNU and cisplatin did not have altered enantioselectivity of thalidomide pharmacokinetics as their basis.

Animals↗
PubMedDate not supplied

Thalidomide in human immunodeficiency virus (HIV) patients. A review of safety considerations.

The sedative thalidomide was withdrawn from the market 30 years ago because of its teratogenic and neurotoxic adverse effects. The compound was later discovered to be extremely effective in the treatment of erythema nodosum leprosum, a complication of lepromatous leprosy. This effect is probably due to a direct influence on the immune system, because thalidomide possesses no antibacterial activity. The compound is presently used as an experimental drug in the treatment of a variety of diseases with an autoimmune character, including recurrent aphthosis of nonviral and nonfungal origin in human immunodeficiency virus (HIV) patients. This article reviews the most important chemical and pharmacokinetic properties of thalidomide. The possible mechanisms of the nonsedative effects of thalidomide with respect to the safety of its use in HIV patients are discussed. Because the mechanism of the immunomodulatory effect of thalidomide is unknown, the possibility that the administration of this compound will accelerate the deterioration of the immunological status of HIV patients cannot be excluded. Clinical evidence suggests that thalidomide may aggravate the condition of patients with preexisting peripheral neuropathy. Hypersensitivity reactions to thalidomide may occur more frequently in HIV patients than in other patient groups. Because of the teratogenic activity of thalidomide, reliable contraception must be provided to female patients of childbearing age. Before the introduction of thalidomide therapy to an HIV patient presenting with oral ulcers, a fungal or viral origin of the lesions should be excluded. Thalidomide should not be used in patients with preexisting HIV-related peripheral polyneuropathy, polyradiculopathy or encephalopathy. In patients experiencing a complete remission, the discontinuation of thalidomide treatment and its reintroduction in the case of a relapse are preferable to maintenance therapy.

Female↗
PubMed2001

Thalidomide use: past history and current implications for practice.

PURPOSE/OBJECTIVES: To review the history of thalidomide, examine fears emanating from its renewed usage, and discuss the nurse's critical role in patient education. DATA SOURCES: Published articles, abstracts, books, and clinical experience. DATA SYNTHESIS: In the early 1960s, the teratogenic effects of thalidomide became widely known. The words thalidomide and birth defects became permanently linked as a result of pregnant women who used thalidomide as a sedative, thus giving birth to children with horrific birth defects. As researchers look at novel properties of drugs and new indications in the oncologic setting, thalidomide has made a comeback, particularly in the treatment of multiple myeloma. Patient education is important to combat fear in using and prescribing thalidomide and is essential in preventing birth defects and other side effects associated with thalidomide use. CONCLUSIONS: Nurses are vital in the patient-education process, yet on extensive nursing literature search revealed limited publications regarding thalidomide. Nurses can prevent thalidomide-associated birth defects through comprehensive patient education and can assist patients in decreasing any anxiety related to potential and actual side effects. IMPLICATIONS FOR NURSING PRACTICE: With careful patient monitoring and comprehensive education of physicians, nurses, and patients, it is possible to reap the benefits of thalidomide and avoid the tragedy of misues. Nurses are in the forefront of education, and their expertise will empower patients to use thalidomide responsibly.

Angiogenesis Inhibitors↗
PubMed2005

Thalidomide therapy and polyneuropathy in myeloma patients.

Thalidomide is today an increasingly used therapy in advanced and refractory myeloma patients, especially in patients relapsing after high dose therapy. One important and well-known side effect of thalidomide is polyneuropathy (PNP). The purpose of this study was to investigate 1) how severe the thalidomide-induced PNP is in patients treated for myeloma 2) which neurophysiological tests and parameters are most sensitive in detecting the thalidomide-induced PNP and 3) how neuropathic symptoms correlate with neurophysiological changes. Twelve patients received thalidomide for treatment of relapsed multiple myeloma for at least 5 months. Prior to the thalidomide treatment, all patients had been treated with chemotherapy including vincristine, and seven patients had also received cisplatin. PNP symptoms, clinical findings and neurophysiological tests before and after the therapy were evaluated. Prior to thalidomide treatment, 7 patients had minimal and one patient slight PNP. After thalidomide treatment, 4 patients had minimal, 4 patients slight, and 3 patients moderate PNP. Thalidomide-induced PNP mainly affected sensory myelinated axons, but also alpha motor neuron axons were affected to some extent. Thermal thresholds were not altered, indicating that thin myelinated and unmyelinated axons are spared. The most sensitive parameter for detecting thalidomide-induced PNP was the sensory nerve compound action potential amplitude. The neuropathic symptoms deteriorated significantly during the therapy, but clinically, no patient developed a disabling PNP that would have required interrupting the therapy. The neuropathic side effects of thalidomide seem to be acceptable in myeloma patients.

Action Potentials↗
PubMed2006

Thalidomide versus placebo in myeloid metaplasia with myelofibrosis: a prospective, randomized, double-blind, multicenter study.

BACKGROUND AND OBJECTIVES: In non-randomized studies, thalidomide appeared to be effective in myeloid metaplasia with myelofibrosis (MMM). We compared thalidomide to placebo for treatment of anemia in MMM. DESIGN AND METHODS: A prospective phase II B, randomized double-blind multicenter trial comparing thalidomide 400 mg/d with placebo for 180 days was conducted in 52 anemic patients (hemoglobin pounds Sterling 9 g/dL or transfused). The main outcome measure was a 2 g/L increase in hemoglobin or 20% reduction in transfusions. RESULTS: In the thalidomide group only 10 patients completed 6 months of treatment. At 180 days, in an intention-to-treat analysis, no difference was observed between the thalidomide and placebo groups as regards improvement of hemoglobin levels (one patient in each group) or reduction of red blood cell transfusions (three vs five patients, respectively). The spleen size, determined by ultrasonography, increased significantly less in the thalidomide group than in the placebo group (p < 0.05). Thalidomide had no apparent benefit on the Dupriez score, the severity score, survival, death, or any other clinical or biological parameter. Somnolence, gastro-intestinal signs, weight gain, and edema were significantly more frequent in the thalidomide group. Outpatient discontinuation of thalidomide was significantly correlated with a high severity score > 4 (odds ratio, OR = 16; p < 0.01), and g-glutamyl transferase levels > 40 IU/L (OR = 12; p < 0.05). INTERPRETATION AND CONCLUSIONS: Thalidomide (200-400 mg/d) does not demonstrate substantial efficacy in anemic MMM patients. The natural history of disease in the placebo group revealed spontaneous periods of remission of anemia. Tolerance of thalidomide was significantly correlated wih the severity and liver involvement of the disease.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Immunomodulation by thalidomide: systematic review of the literature and of unpublished observations.

Three decades of immunological investigations using thalidomide are reviewed. Both in vitro and in vivo investigations are in accordance with the clinical finding that thalidomide does not impede T-cell competence in the control of infection by mycobacteriae. The term immunosuppressant does not apply. The immunomodulatory effects of thalidomide are evident in a myriad of phenomenological changes, and a molecularly defined common denominator of these activities is not known at present. Critical assessment with the objective to account for the clinical activity of thalidomide in specific human diseases leads to a focus on effects of thalidomide on phagocytic leukocytes and endothelia. The former are responsive to thalidomide by modulation of cytokine synthesis in vitro and in vivo; this activity can be shown using monocyte-specific stimuli in peripheral blood mononuclear cells but also in other phagocytic cells like microglia. For technical reasons, endothelial cells have until now been tested primarily in vitro. However, there is solid evidence now from intravital microscopy that the induction of adhesivity in postcapillary venules by LPS is modulated by thalidomide. Altered surface antigen expression has been described on leukocytes obtained from humans and experimental animals treated with thalidomide, but convincing evidence is lacking for in vitro modulation of surface antigen expression on leukocytes (as opposed to the modulation of adhesion antigens on endothelial cells stimulated by LPS or exogenous TNF alpha in the presence of thalidomide). Therefore, in vivo redistribution is likely to account for some, if not all, changes in circulating leukocyte phenotypes. The immunopathological conditions most clearly responsive to thalidomide are vasculitic alterations of post-capillary venules either in the context of mycobacterial infection (in the case of erythema nodosum leprosum) or mucocutaneous aphths. In both instances (as in the majority of focal inflammatory lesions), leukocyte infiltration and cytokine responses, in particular TNF alpha, are present. Thalidomide acts clinically not only by palliation of existing lesions but also by prevention of recurrence. The mechanism operates in skin, mucosa and parts of the nervous system and is most readily explained by synergism of TNF alpha modulation and a separate point of action on leukocyte migration patterns.

Adjuvants, Immunologic↗
PubMed2005

Effect of thalidomide on colorectal cancer liver metastases in CBA mice.

BACKGROUND AND AIMS: Thalidomide has undergone resurgence in the treatment of specific malignancies. One of the possible actions of thalidomide may be an antiangiogenic effect. This study investigates the effects of thalidomide on tumor growth and long-term survival in a murine model of colorectal liver metastases. METHODS: Liver metastases were produced in male CBA mice by intrasplenic injection of a dimethyl hydrazine induced MoCR colon cancer murine cell line. Thalidomide was administered daily at doses ranging from 50 to 300 mg/kg by intraperitoneal injection. Tumor growth was assessed using quantitative stereological analysis. The effect on long-term survival was determined at the maximum tolerated dose using Kaplan-Meier analysis. The microvascular effects of thalidomide were assessed by laser Doppler flowmetry (LDF) and microvascular resin casting. Immunohistochemistry was used to determine vascular endothelial growth factor (VGEF) and basic fibroblast growth factor (bFGF) expression. RESULTS: Thalidomide, (50-300 mg/kg) caused no significant reduction in tumor growth by day 21 following induction of liver metastases and caused systemic toxicity at a dose of 300 mg/kg. At a dose of 200 mg/kg given beyond 35 days, thalidomide significantly reduced tumor growth compared to control, (P = 0.029). No significant impact on survival was however observed (P = 0.93). LDF and microvascular resin casting showed no differences in blood flow or tumor microvascular architecture. VGEF and FGF were expressed in tumors, but remained unaltered by thalidomide administration compared to matched controls. CONCLUSIONS: Thalidomide caused a significant reduction in the volume of colorectal liver metastases during the late phase of tumor growth. There was however no improvement in survival. Tumor growth reduction in this model did not appear to be due to microvascular changes or altered expression of VGEF or basic FGF. Further investigation into potential mechanisms of action of thalidomide and its synergistic use with other therapies is required.

Analysis of Variance↗
PubMed2007

Preventive and therapeutic anti-inflammatory effects of systemic and topical thalidomide on endotoxin-induced uveitis in rats.

The present study examined the outcomes of systemic or topical treatment with thalidomide, a compound that possesses anti-inflammatory, immunomodulatory and anti-angiogenic properties, in rats subjected to endotoxin-induced uveitis (EIU). The effects of thalidomide were evaluated on endotoxin-induced leucocyte and protein infiltration and also on the production of interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha in rat aqueous humour (AqH). Moreover, the actions of thalidomide were assessed on the cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) protein expression in retinal tissue. EIU was produced by a hindpaw injection of lipopolysaccharide (LPS), in male Wistar rats. Thalidomide (5, 25 and 50 mg/kg) was administered orally 1 h before LPS injection. In another set of experiments, to evaluate the therapeutic efficacy, 5% thalidomide was applied topically to both eyes at 6, 12 and 18 h after LPS administration. The oral pre-treatment with thalidomide decreased, in a dose-dependent manner, the number of inflammatory cells, the protein concentration, and the levels of IL-1beta and TNF-alpha in the AqH. Similar results were found in the AqH of rats that received a topical application of thalidomide. Furthermore, oral (50 mg/kg) and local (5%) thalidomide treatment also reduced expression of the pro-inflammatory proteins COX-2 and iNOS in the posterior segment of the eye. Thalidomide exhibited marked preventive and curative ocular effects in EIU in rats, a property that might be associated with its ability to inhibit the production of inflammatory cytokines and the expression of COX-2 and iNOS. This assembly of data provides additional molecular and functional insights into beneficial effects of thalidomide as an agent for the management of ocular inflammation.

Administration, Oral↗
PubMed1999

Thalidomide does not alter estrogen-progesterone hormone single dose pharmacokinetics.

OBJECTIVES: To determine the single- and multiple-dose pharmacokinetics of oral thalidomide (200 mg/day, administered for 21 days) and to assess the effects of steady-state plasma concentrations of thalidomide on the single-dose pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: A randomized, 2-period crossover study was performed in 10 healthy premenopausal female volunteers. The pharmacokinetic profiles of plasma concentrations of thalidomide were evaluated with both noncompartmental and compartmental methods, whereas those of ethinyl estradiol and norethindrone were calculated with noncompartmental methods. The effects of steady-state plasma thalidomide concentrations on the pharmacokinetics of ethinyl estradiol and norethindrone were determined with use of an ANOVA model that included treatment sequence, subject within sequence, period, and treatment as factors. RESULTS: Thalidomide plasma concentrations were best predicted by a 1-compartment model with first-order absorption and elimination and an absorption time-lag. There were no significant differences between pharmacokinetic parameters for thalidomide after 1 dose and those after 18 consecutive doses. Except for a minor decrease of the elimination rate constant (k(e)) for ethinyl estradiol, coadministration of thalidomide had no significant effects on the pharmacokinetic profiles for either ethinyl estradiol or norethindrone. The change in k(e) for ethinyl estradiol during thalidomide administration was not associated with any alteration in the clearance or elimination half-life for this hormone. CONCLUSIONS: Multiple-dose pharmacokinetics of thalidomide is similar to the single-dose profile. This study did not investigate the efficacy of the 21-day fixed ethinyl estradiol-norethindrone regimen, but the results suggest that thalidomide is unlikely to affect the pharmacokinetics of orally administered hormonal contraceptives.

Administration, Oral↗
PubMed2003

Dermatologic side effects of thalidomide in patients with multiple myeloma.

BACKGROUND: Thalidomide, an antiangiogenic agent, was approved by the Food and Drug Administration in 1998 for the treatment of erythema nodosum leprosum. Although its teratogenic and neurologic side effects are well known, its dermatologic side effects continue to be defined. OBJECTIVE: We report the dermatologic side effects in 87 patients with multiple myeloma enrolled in a comparative, open-label, clinical trial treated with thalidomide alone (50 patients) or thalidomide and dexamethasone (37 patients). METHOD: We reviewed the records of all patients enrolled in the clinical trial. The frequency, type, severity, and time of onset of all skin eruptions that were temporally related to thalidomide treatment were recorded. RESULTS: Minor to moderate skin eruptions were noted in 46% of patients taking thalidomide alone and in 43% of those taking thalidomide and dexamethasone. These included morbilliform, seborrheic, maculopapular, or nonspecific dermatitis. Severe skin reactions (exfoliative erythroderma, erythema multiforme, and toxic epidermal necrolysis) that required hospitalization and withdrawal of thalidomide developed in 3 patients receiving thalidomide and dexamethasone. CONCLUSION: The prevalence of dermatologic side effects of thalidomide appear to be higher than previously reported. Although in most patients they were minor, in a few patients they were quite severe, particularly when given in conjunction with dexamethasone for newly diagnosed myeloma. Further studies are needed to verify the extent of the interaction between thalidomide and dexamethasone in this group of patients.

Adult↗
PubMed1995

Thalidomide as treatment of refractory aphthous ulceration related to human immunodeficiency virus infection.

In recent years, thalidomide has been used for the treatment of a variety of ulcerative and immunologic conditions. Several previous reports have suggested that thalidomide therapy is beneficial for patients with aphthous ulceration related to human immunodeficiency virus (HIV) infection. We describe the use of thalidomide in 20 HIV-infected patients with oropharyngeal, esophageal, and rectal ulceration. Nineteen patients had a dramatic response to thalidomide therapy, with both subjective and objective abatement in the signs and symptoms of their ulcerative disease. The standard treatment course was 200 mg of thalidomide for 14 days (the drug was administered at night). Four patients required additional courses of treatment because symptoms recurred after thalidomide therapy was stopped. Side effects due to thalidomide included rash (5 patients), peripheral neuropathy (1 patient), and excessive fatigue (1 patient). There did not appear to be any adverse immunologic effects in thalidomide-treated patients. The mechanism of the effect of thalidomide is uncertain, although recent studies have suggested that thalidomide selectively inhibits the production of tumor necrosis factor alpha.

Adult↗