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PubMed1977

A comparison of thalidomide and pentobarbital - new methods for identifying novel hypnotic drugs.

We have compared the sleep-producing effects of thalidomide and pentobarbital. In a dose range that did not produce ataxia, thalidomide increased slow wave sleep and rapid eye movement sleep in cats (2-8 mg/kg p.o.) and rats (16 mg/kg p.o.). Pentobarbital had hypnotic activity in the same dose range but produced ataxia also at these doses. Thalidomide reduced spontaneous activity of both mice and rats. This occurred over a dose range of 8 to 1000 mg/kg p.o., but plateaued at a level of activity well above the complete inactivity of anesthesia that occurred with pentobarbital at well above the complete inactivity of anesthesia that occurred with pentobarbital at doses (greater than or equal to 32 mg/kg p.o.) above the hypnotic range. Several simple screens for thalidomide-like activity have been described which, together, could facilitate the search for thalidomide-like hypnotics. Pentobarbital, at doses 3 to 10 times the hypnotic range, prevented audiogenic seizures in physically dependent rats withdrawn from sodium barbital but thalidomide did not substitute for barbiturates even at doses 30 times those that increased sleep. Thalidomide, but not pentobarbital, enhanced the sleep-producing effect of electrical stimulation of basal forebrain in cats. The latter two findings suggest that thalidomide probably has a mechanism of action different from that of pentobarbital and that this may involve the activation of a sleep center in the forebrain.

Animals↗
PubMed1995

Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis.

BACKGROUND: The monocyte-derived cytokine, tumor necrosis factor alpha (TNF alpha), is essential for host immunity, but overproduction of this cytokine may have serious pathologic consequences. Excess TNF alpha produced in pulmonary tuberculosis may cause fevers, weakness, night sweats, necrosis, and progressive weight loss. Thalidomide (alpha-N-phthalimidoglutarimide) has recently been shown to suppress TNF alpha production by human monocytes in vitro and to reduce serum TNF alpha in leprosy patients. We have therefore conducted a two-part placebo-controlled pilot study of thalidomide in patients with active tuberculosis to determine its effects on clinical response, immune reactivity, TNF alpha levels, and weight. MATERIALS AND METHODS: 30 male patients with active tuberculosis, either human immunodeficiency virus type 1 positive (HIV-1+) or HIV-1-, received thalidomide or placebo for single or multiple 14 day cycles. Toxicity of the study drug, delayed type hypersensitivity (DTH), cytokine production, and weight gain were evaluated. RESULTS: Thalidomide treatment was well tolerated, without serious adverse events. The drug did not adversely affect the DTH response to purified protein derivative (PPD), total leukocyte, or differential cell counts. TNF alpha production was significantly reduced during thalidomide treatment while interferon-gamma (IFN gamma) production was enhanced. Daily administration of thalidomide resulted in a significant enhancement of weight gain. CONCLUSIONS: The results indicate that thalidomide is well tolerated by patients receiving anti-tuberculosis therapy. Thalidomide treatment reduces TNF alpha production both in vivo and in vitro and is associated with an accelerated weight gain during the study period.

Adult↗
PubMed1996

Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-host disease.

Thalidomide has been reported to be an effective agent for the treatment of chronic graft-vs.-host disease (GVHD). To determine its efficacy as a prophylactic agent for the prevention of chronic GVHD, a prospective randomized double-blind study was performed. A total of 59 patients were randomized to receive either placebo or thalidomide (200 mg orally twice a day) beginning 80 days after allogeneic bone marrow transplantation (BMT). Fifty-four evaluable patients were analyzed, 26 received placebo, and 28 received thalidomide. The characteristics of patients were well-balanced between the two groups. Following the first interim analysis conducted by the Data Safety Monitoring Board using an intent-to-treat approach, a statistically significant difference in the incidence of chronic GVHD was found. Patients receiving thalidomide developed chronic GVHD more often than patients receiving placebo (p = 0.06). Moreover, an apparent overall survival advantage was noted for patients receiving placebo compared to those receiving thalidomide (p = 0.006). Adjustment for possible confounding factors did not eliminate these negative effects of thalidomide. These results demonstrate that while thalidomide is an effective agent for the therapy of chronic GVHD, its use at the doses administered for the prophylaxis of chronic GVHD resulted in a paradoxical outcome with a higher incidence of chronic GVHD and a lower overall survival. We conclude that the early use of thalidomide results in a shift in the balance between GVHD and induction of tolerance. These data demonstrate again the importance of phase III double-blind controlled randomized studies.

Adolescent↗
PubMed2002

40 years later: the health related quality of life of women affected by thalidomide.

OBJECTIVES: 40 years ago, the sudden increase of births of babies with a range of severe deformities shocked the world. It was caused by the tranquilizer thalidomide. Women who took the drug in the first trimester of pregnancy gave birth to children with a wide but distinctive range of malformations. Thalidomide claimed more than 10,000 victims worldwide. Those who survived are now reaching middle age. Especially women affected by thalidomide may be at special disadvantage because of combined discrimination based on gender and disability. So far, no study has been published that has investigated their quality of life in health and in health care. METHODS: A questionnaire using the WHO QOL-BREF instrument for measuring health-related quality of life was distributed among 166 females impaired by thalidomide. A randomized control group matched by age, sex and area of residence filled out a corresponding questionnaire. RESULTS: Women impaired by thalidomide reported significantly lower quality of life in health and health care as compared to their control group. Over a third reported steadily deteriorating conditions, and a statistically significant higher proportion as compared to the controls has already retired from the workforce. They were significantly less frequently married, had fewer children, had less household incomes and were less mobile. However, women impaired by thalidomide are more likely to be satisfied with their safety in daily life, with their physical environment, with their living conditions and with the support they get from their friends. CONCLUSIONS: Although there is increasing clinical research on how to use thalidomide as a drug in new therapies, the specific health needs of women impaired by thalidomide are at risk of being neglected.

Journal Article↗
PubMed1996

Thalidomide, a current teratogen in South America.

Thalidomide, mainly used for the treatment of leprosy, is a current teratogen in South America, and it is reasonable to assume that at present this situation is affecting many births in underdeveloped countries. Moreover, the potential re-marketing of thalidomide for the treatment of a large variety of diseases may extend the problem to the developed world. When the drug is available, the control of its intake during early pregnancy is very difficult since most pregnancies are unintended. The ongoing occurrence of thalidomide embryopathy cases went undetected by the ECLAMC, due to several factors: (1) low populational coverage through this monitoring system; (2) pre-existence of the teratogen with its effects present in both baseline (expected) and monitored (observed) materials; and (3) lack of a defined phenotype to be monitored. Thus, if thalidomide re-enters the market throughout the world, due to the wide range of new applications, occurrence of phocomelia alone might not be sufficient to detect its effects. By a case-reference approach, the ECLAMC registered 34 thalidomide embryopathy cases born in South America after 1965 whose birthplaces correspond to endemic areas for leprosy. Phocomelia was found in five of eleven fully described cases. Thus, phocomelia alone is neither specific nor sufficient to serve as a suitable phenotype to survey the teratogenic effects of thalidomide. Therefore, a thalidomide-like phenotype, defined as any bilateral upper and/or lower limb reduction defect of the preaxial and/or phocomelia types, should be included in the routine surveillance of birth defects in all programmes.

Abnormalities, Drug-Induced↗
PubMed2000

The re-emergence of thalidomide: results of a scientific conference.

BACKGROUND: The use of thalidomide during the 1950s resulted in teratogenic effects in thousands of infants. Although thalidomide is currently approved for the treatment of a complication of leprosy, it is commercially available to treat other diseases through a controlled distribution system. This article presents a summary of a scientific conference organized to assess clinical research on thalidomide, its new clinical applications, and the social and ethical implications for its use. METHODS: Summaries of 10 presentations and two panel discussions were developed from the authors's, oral presentations, conference slides, responses to questions, and supporting literature. RESULTS: Thalidomide shows promise in treating several diseases, including HIV/AIDS, rheumatoid arthritis, Crohn's disease, and multiple myeloma. The STEPStrade mark (System for Thalidomide Education and Prescribing Safety) Program has been developed by Celgene, the commercial manufacturer of thalidomide, to ensure compliance with prescription and usage protocols. A surveillance system is also in place to monitor and report compliance patterns. CONCLUSIONS: Despite the tragic past associated with thalidomide, the drug shows promise as a treatment for many clinical disorders. The challenge is to answer lingering questions of risks and benefits through clinical trials and discovery, to monitor participation and compliance with protocols developed to avoid use of the drug during pregnancy, and to continue to search for safer and more effective treatment options.

Abnormalities, Drug-Induced↗
PubMed2000

Assessment of the in vitro and in vivo genotoxicity of Thalomid (thalidomide).

Thalomid is the FDA-approved commercial formulation of thalidomide currently used in the US to treat erythema nodosum leprosum, a complication of leprosy. The genotoxicity of Thalomid thalidomide was assessed in the Ames reverse mutation, AS52/XPRT mammalian cell forward gene mutation, and mouse bone marrow micronucleus assays. The Ames and AS52 assays were performed with and without S9. In the Ames, Salmonella typhimurium strains TA1535, 1537, 98, 100, and 102 and Escherichia coli strain WP2 uvrA were used. Assays were performed by using plate incorporation and liquid pre-incubation systems at thalidomide doses of 50-10,000 microg/plate. In the AS52 assay, Chinese hamster ovary cells were plated with fortified Ham's F12 medium and incubated overnight. The medium was then incubated with 1-1000 microg/ml thalidomide. After a series of aspirations, washings, reconstitutions, and incubations, mutant AS52 cells were fixed and stained. Colonies were then counted and the relative survival frequencies compared to negative controls. In the mouse micronucleus assay, Crl:CD-1 albino mice were dosed with 500, 2,500, and 5,000 mg/kg thalidomide and sacrificed over 72 h. Femurs were flushed with fetal bovine serum and the suspensions centrifuged. The supernatant was aspirated and the cell pellet resuspended and stained. Polychromatic erythrocytes were scored for micronucleated polychromatic and normochromatic erythrocytes. Thalidomide did not increase revertant frequencies in all bacterial strains. It also did not produce any significant increase in the average mutant frequencies of AS52 cells and mouse micronucleated polychromatic erythrocytes. We conclude that Celgene's Thalomid thalidomide is non-genotoxic.

Animals↗
PubMed2001

Thalidomide-associated hepatitis: a case report.

We report a case of hepatitis in a 58-year-old woman being treated with thalidomide for end-stage plasma cell leukemia. The patient had a medical history including chronic stable hepatitis C infection. At diagnosis there was a severe anemia, thrombocytopenia, hypercalcemia, IgG paraproteinemia, peripheral blood myeloma cells, and a marrow plasmacytosis with lytic bony lesion. The disease was refractory to standard chemotherapy, and she was treated with oral thalidomide. Within 1 week she became jaundiced and developed a marked transaminitis. This promptly resolved upon cessation of thalidomide alone. Thalidomide has recently enjoyed renewed interest as a treatment in many disorders, including plasma cell leukemia. To our knowledge, this is the first reported case of thalidomide-associated hepatotoxicity. Although the mechanism of its actions on the liver are uncertain, it is possible that thalidomide acts as a direct hepatotoxin or as an immuno-modulator, altering the activity of chronic viral hepatitis. We present this case to increase awareness of a new potential side effect of thalidomide as its clinical indications expand.

Antineoplastic Agents↗
PubMed1995

Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide.

The purposes of this work were (1) to develop a high performance liquid chromatographic (HPLC) assay for the enantiomers of thalidomide in blood, (2) to study their inversion and degradation in human blood, and (3) to study the pharmacokinetics of (+)-(R)- and (-)-(S)-thalidomide after oral administration of the separate enantiomers or of the racemate to healthy male volunteers. The enantiomers of thalidomide were determined by direct resolution on a tribenzoyl cellulose column. Mean rate constants of chiral inversion of (+)-(R)-thalidomide and (-)-(S)-thalidomide in blood at 37 degrees C were 0.30 and 0.31 h-1, respectively. Rate constants of degradation were 0.17 and 0.18 h-1. There was rapid interconversion in vivo in humans, the (+)-(R)-enantiomer predominating at equilibrium. The pharmacokinetics of (+)-(R)- and (-)-(S)-thalidomide could be characterized by means of two one-compartment models connected by rate constants for chiral inversion. Mean rate constants for in vivo inversion were 0.17 h-1 (R to S) and 0.12 h-1 (S to R) and for elimination 0.079 h-1 (R) and 0.24 h-1 (S), i.e., a considerably faster rate of elimination of the (-)-(S)-enantiomer. Putative differences in therapeutic or adverse effects between (+)-(R)- and (-)-(S)-thalidomide would to a large extent be abolished by rapid interconversion in vivo.

Adult↗
PubMed2006

Phase I/II study of thalidomide in combination with interleukin-2 in patients with metastatic renal cell carcinoma.

BACKGROUND: The purpose of the study was to determine, in a Phase I/II study, the efficacy and safety profile of thalidomide with interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma (MRCC). METHODS: Fifteen patients (8 of whom were previously treated) enrolled in Phase I were treated with escalating doses of oral thalidomide (200-600 mg) and a fixed dose of IL-2 (7 mIU/m(2)) by subcutaneous injection. A course was 6 weeks, with the exception of Course 1, which was 7 weeks. Thirty-seven Phase II patients who had not received prior chemotherapy or immunotherapy for renal cell carcinoma (RCC) received an initial thalidomide dose of 200 mg at Week 0, which was escalated to 400 mg after 48 hours. Subcutaneous IL-2 was administered at the same fixed daily dose used in Phase I. RESULTS: Fifty-one of 52 Phase I/II patients were evaluable. Twenty-seven patients (52%) experienced disease control, including 4 (8%) complete responses, 15 (29%) partial responses, and 8 (15%) cases of stable disease. Disease progression was observed in 24 patients (47%). Survival in the 2 phases ranged from 4 weeks to 45.2+ months. At the time of last follow-up, 2 of 51 patients (4%) remained on maintenance thalidomide therapy and continue to be followed. Three of the 51 patients with CRs (6%) ceased thalidomide therapy at 23-25 months and have maintained their responses to date. One complete responder was lost to follow-up. As of January 2005, 14 of 51 patients (27%) remained alive. Toxicities were mild to moderate, including Grade 1 to 2 somnolence, constipation, neuropathy, rash, flu-like symptoms, fluid retention, hypotension, and hypothyroidism (according to version 2.0 of National Cancer Institute Common Toxicity Criteria). In addition, two patients experienced deep venous thrombosis. CONCLUSIONS: Thalidomide in combination with IL-2 is tolerable and can produce durable, active responses in patients with MRCC. To evaluate the merits of thalidomide as a valuable agent against MRCC and to more fully determine the efficacy of thalidomide/IL-2 combination therapy, the scrutiny of Phase III testing is required. Further development of thalidomide/IL-2 combination therapy will be the focus of this group.

Administration, Oral↗
PubMed1985

Teratogen update: clinical aspects of thalidomide embryopathy--a continuing preoccupation.

There is much misinformation in the medical community regarding the thalidomide syndrome. Some physicians and scientists are unaware of the fact that organs other than the limbs were frequently affected. Some believe that thalidomide could produce any type of limb reduction defect. Most were aware of the very narrow period of early organogenesis during which the thalidomide-type malformations could be produced. Important features include the fact that limb reduction defects were primarily preaxial, included concomitant girdle hypoplasia when limb reductions were severe, were almost universally bilateral and did not include distal transverse-type defects often called "hemimelia". While it can be said that some spontaneous (non-thalidomide) malformations can mimic the thalidomide syndrome, it can also be said that many limb reduction defects can be determined not to have been produced by thalidomide. The risks of the various defects can be estimated following exposure, with most certainty for limb defects, with less certainty for other defects. Many defects were not associated with exposure to thalidomide such as cleft lip and severe mental retardation.

Abdomen↗
PubMed2000

Immune stimulation in scleroderma patients treated with thalidomide.

Scleroderma (SSc) is a fibrosing connective tissue disease that is poorly responsive to any treatment, including immune suppression. SSc shares many characteristics with chronic graft-versus-host disease (GVHD). Because the immunomodulatory drug thalidomide has proven beneficial in chronic GVHD, we studied the immune response and clinical effects of thalidomide in SSc patients. We treated 11 SSc patients with thalidomide in an open label, dose escalating, 12 week study. Histologic comparison of skin biopsies showed changes in skin fibrosis and an increase in epidermal and dermal infiltrating CD8(+) T cells with thalidomide treatment. In thalidomide-treated SSc patients, plasma levels of IL-12 and TNF-alpha increased, while plasma IL-5 and IL-10 levels remained unchanged. These changes were associated with clinical effects, including dry skin, dermal edema, transient rashes, decreased gastroesophageal reflux symptoms, and healing of digital ulcers. When SSc PBMCs activated by anti-CD3 mAb were exposed to thalidomide, increases in both production of IL-2, IL-3, GM-CSF, and IFN-gamma and T cell expression of CD40L were observed. Thalidomide therefore appears to induce immune stimulation in SSc patients in association with clinical changes. However, it remains to be shown whether long-term enhancement of immune responses in SSc patients is clinically beneficial.

Adjuvants, Immunologic↗
PubMed2002

Thalidomide in chronic graft-versus-host disease after stem cell transplantation: effects on quality of life.

Thalidomide is being increasingly used after stem cell transplantation as immunosuppression for patients with chronic graft-versus-host disease, as well as for antiangiogenesis effects in patients with multiple myeloma, brain tumors, leukemia, or other malignancies. The goal of this study was to determine if thalidomide improved the quality of life by virtue of its associated sleep-promoting, anxiety-reducing, antiwasting, and antidiarrheal effects. We therefore studied 28 patients with resistant chronic graft-versus-host disease who were treated with thalidomide (13 patients) or other immunosuppressive drugs (15) and compared them with healthy control subjects (16). All patients completed quality-of-life questionnaires prospectively before beginning regimens of thalidomide or other immunosuppressive drugs and completed similar questionnaires at 3- and 6-month intervals thereafter. The Transplant Symptom Frequency score was similar for healthy control subjects and both groups of patients with chronic graft-versus-host disease, regardless of whether they had received thalidomide or not. Quality of sleep was equally poor in patients who received or did not receive thalidomide. The most common complaint of patients with chronic graft-versus-host disease was fatigue, followed in frequency by overeating. The control group had similar concerns. This pilot study suggests that patients with chronic graft-versus-host disease have a quality of life similar to that of their health care workers, regardless of whether they are treated with thalidomide or other immunosuppressive drug, and that fatigue and overeating are the most common complaints.

Case-Control Studies↗
PubMed2006

Thalidomide increases in vitro sensitivity of childhood acute lymphoblastic leukemia cells to prednisolone and cytarabine.

INTRODUCTION: Thalidomide is a derivative of glutamic acid with anti-angiogenic, anti-inflammatory, immunomodulatory and anti-cancer properties that was found to inhibit the production of tumor necrosis factor alpha in vitro, stimulate reactive oxygen species production, and inhibit vascular endothelial growth factor receptor in acute leukemias. The purpose of this study was to determine the in vitro activity of thalidomide as a single agent and in combination with prednisolone or cytarabine in childhood acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Bone marrow samples of 40 childhood ALL patients, normal lymphocytes of 9 healthy adults, and 3 lymphoid cell lines were evaluated for cytotoxicity of thalidomide (alone and in combination with prednisolone and cytarabine) using the MTT assay. Cell cycle analysis was performed by flow cytometry. RESULTS: Thalidomide as a single agent had weak antileukemic activity to the childhood ALL samples. However, in the presence of thalidomide the cytotoxicities of prednisolone and cytarabine were increased 3.3-fold (p<0.001) and 2.7-fold (p=0.002), respectively. Thalidomide increased apoptosis in lymphoblasts and modulated the cell-cycle arrest caused by prednisolone, but not that by cytarabine, in childhood ALL samples. CONCLUSIONS: Thalidomide increases in vitro the sensitivity of childhood ALL cells to prednisolone and cytarabine.

Adolescent↗
PubMed2006

Lovastatin and thalidomide have a combined effect on the rate of multiple myeloma cell apoptosis in short term cell cultures.

OBJECTIVE: Multiple myeloma is characterized by an accumulation of plasma cells in bone marrow. Despite many therapeutic regimens introduced recently, the prognosis for patients suffering from treatment-resistant or relapsing multiple myeloma is still very poor. Thus, there is an urgent medical need for novel innovative drugs. Thalidomide is successfully used in resistant or relapsing myeloma patients, being reported to induce apoptosis or G1 growth arrest of myeloma cells and to regulate microvessel density and cytokine secretion. Lovastatin, largely used for the treatment of hypercholesterolemia, is another promising drug in multiple myeloma. High doses of lovastatin have been shown to have antiproliferative effect by inhibition of malignant cell proliferation and inducing programmed cell death. METHODS: In this study, we tried to assess whether thalidomide and lovastatin had a combined effect on apoptosis of myeloma cells. We analyzed apoptosis induced by mixture of these two drugs in short-term cell culture of myeloma plasmocytes. To assess apoptosis, we used Annexin V and propidium iodide binding. We also examined the regulation of BCL-2 and BAX protein expression in the population of CD138+ plasmocytes. The cells were analyzed with the use of flow cytometry technique. The experiments were done before and after 72 h of cell culture. RESULTS: We detected a higher rate of apoptosis induced by lovastatin and thalidomide mixture in comparison to apoptosis induced by lovastatin or thalidomide alone. In most patients, the BCL-2/BAX ratio was lower in cell cultures supplemented with mixture of lovastatin and thalidomide in comparison with cell cultures supplemented with lovastatin or thalidomide alone. CONCLUSION: Based on our research we conclude that the mixture of lovastatin and thalidomide may increase the rate of multiple myeloma cells apoptosis in comparison to the single drug and the precise mechanism of this effect should be approved by further research.

Apoptosis↗
PubMed2003

Structural development of synthetic retinoids and thalidomide-related molecules.

The full-scale commercial appearance of antibiotics in the 1950s caused a shift in the nature of lethal diseases from infectious and acute to noninfectious and chronic. In this situation, biological response modifiers (BRMs), which are not based on selective toxicity, could be expected to be useful. Several types of BRM exist, including retinoids, which act directly on cells at the level of gene expression, and thalidomide and related molecules, which modulate the production of various cytokines. We have been engaged in medicinal, chemical, and structural development studies based on these bioactive compounds. Retinoids include all- trans-retinoic acid (ATRA), a major active form of vitamin A (retinol), and its bioisosters, which elicit their biological effects by binding to their nuclear receptors, retinoic acid receptors (RARs). ATRA has been used in differentiation therapy, typically for the treatment of acute promyelocytic leukemia, and the treatment of dermatological diseases. Our structural development studies of retinoids, including computer-assisted molecular design, have yielded class/subtype-selective agonists, synergists, and antagonists of RARs and their partner nuclear receptors, retinoid X receptors. Among them, the benzanilide-type compounds, Am80 and TAC101, are under phase II and I/II clinical studies in Japan and the USA, respectively. Thalidomide is a hypnotic/sedative drug that was withdrawn from the market because of teratogenicity. However, thalidomide has been established to be useful in the treatment of various diseases including cancer. Thalidomide elicits a wide range of pharmacological effects, including anticachexia, anti-tumor-promoting, antiangiogenic, immunosuppressing, antiviral, hypoglycemic, and antimetastatic activities. We have found that thalidomide is a multitarget drug. Hypothetical target events/molecules of thalidomide include tumor necrosis factor-alpha production, nuclear androgen receptor, cyclooxygenases, aminopeptidases, and alpha-glucosidase. Specific and potent compounds for each of these target phenomena/molecules have been prepared by appropriate modification of the thalidomide structure, and are expected to be superior lead compounds for novel immunomodulators, antiangiogenic agents, and anti-tumor-promoting agents.

Computer Simulation↗
PubMed2001

A difference between the rat and mouse in the pharmacokinetic interaction of 5,6-dimethylxanthenone-4-acetic acid with thalidomide.

PURPOSE: Coadministration of thalidomide, cyproheptadine or diclofenac has been shown to increase the area under the plasma concentration-time curve (AUC) of the novel antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice. The aim of this study was to further investigate these pharmacokinetic DMXAA-drug interactions in the rat model. METHODS: The effects of coadministration of L-thalidomide, cyproheptadine or diclofenac on the pharmacokinetics of DMXAA were investigated in male Wistar Kyoto rats. The effects of L-thalidomide, cyproheptadine and diclofenac on microsomal metabolism and plasma protein binding of DMXAA were also investigated. RESULTS: No significant alteration in the plasma concentration profile for DMXAA was observed following L-thalidomide pretreatment in rats. In contrast, when combined with diclofenac or cyproheptadine, the plasma AUC of DMXAA was significantly (P<0.05) increased by 48% and 88% and the T1/2 by 36% and 107%, respectively, compared to controls. Both diclofenac and cyproheptadine at 500 microM caused a significant inhibition of DMXAA metabolism in rat liver microsomes. In contrast, L-thalidomide had no or little inhibitory effect on DMXAA metabolism in rat liver microsomes except for causing a 32% decrease in 6methylhydroxylation at 500 microM. None of the drugs had a significant effect on the plasma protein binding of DMXAA in the rat. CONCLUSION: These studies showed that coadministration of L-thalidomide did not alter the plasma DMXAA AUC in rats, in contrast to previous studies in mice, whereas diclofenac and cyproheptadine significantly reduced the plasma clearance of DMXAA in rats in a similar manner to their effect in mice. The cause of the species difference in the pharmacokinetic response to thalidomide by DMXAA is unknown, and indicates difficulties in predicting the outcome of such a combination in patients.

Animals↗
PubMed2006

The effect of thalidomide on corticosteroid-dependent pulmonary sarcoidosis.

STUDY OBJECTIVE: To determine the benefit and corticosteroid-sparing potential of thalidomide in corticosteroid-dependent pulmonary sarcoidosis. METHODS: The study was a prospective open-label pilot study. Ten subjects were enrolled who had pulmonary sarcoidosis, required corticosteroid therapy for at least six months, and experienced a flare of pulmonary sarcoidosis within the previous 2 years when corticosteroids had been reduced or discontinued. Thalidomide was given at a dose of 200 mg/day for 24 weeks. Dose reductions were allowed in 50 mg/day increments for side effects. After 12 weeks, the baseline corticosteroid dose was halved for the remaining 12 weeks of the study. RESULTS: There were no clinically or statistically significant changes in spirometry (FVC% predicted: week 0: 72 +/- 4, week 12: 75 +/- 5, week 24: 73 +/- 4; p = NS), quality of life (as measured by the Short Form-36), or dyspnea (as measured by the Transitional Dyspnea Index) between weeks 0, 12, and 24. Three (30%) subjects demonstrated clinical evidence of a corticosteroid-sparing effect from thalidomide. Three (30%) subjects had to withdraw from the study; two at week 4 because of an acute pulmonary flare of sarcoidosis, and one because of possible side effects. Although nine of 10 (90%) of subjects required a reduction of the thalidomide dose because of side effects, no adverse effects were severe. The most common final dose of thalidomide was 100 mg/day. CONCLUSIONS: Thalidomide does not significantly improve pulmonary function or quality of life in patients with corticosteroid-dependent sarcoidosis. Few patients can tolerate doses of greater than 100 mg/day. Thalidomide may have been corticosteroid-sparing in a subgroup of these patients.

Adrenal Cortex Hormones↗