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PubMed2006

Safety and efficacy of thalidomide in recurrent epithelial ovarian and peritoneal carcinoma.

OBJECTIVE: Thalidomide is an anti-angiogenesis agent that has shown activity in some solid tumors. We performed a phase I clinical trial to determine the toxicity and potential efficacy of Thalidomide in recurrent epithelial ovarian carcinoma. METHODS: Patients with recurrent ovarian cancer were evaluated between 1998 and 2000. Data were evaluated using Kaplan-Meier and logistic regression analyses. RESULTS: 17 heavily pretreated patients with recurrent epithelial ovarian cancer received oral Thalidomide starting at 100 mg/day, with dose escalations of 100 mg/day every 2 weeks, up to 1200 mg/day as tolerated. The median number of courses was four (range: 1-18 courses), and median dose was 200 mg/day (range: 100-600 mg/day). Treatment duration ranged from 2 to 48 months. Common grade 1 or 2 side effects included constipation (76%), neuropathy (71%), and fatigue (65%) with few grade 3 or 4 events. Three (18%) patients had partial responses, and six (35%) had stabilization of disease after 6 months. After 1 year of treatment, six of the nine patients with an initial partial response (n=2) or stable disease (n=4) remained in these response categories. Median time to progression was 10 months. Forty-seven percent of patients had a 50-70% decrease in CA125 levels. Using logistic regression and repeated measures analyses, CA125 levels decreased by 62 units/ml per month (p=0.07). CONCLUSION: Our study demonstrates the safety, tolerability, and potential efficacy of Thalidomide in recurrent and refractory epithelial ovarian cancers. Additional clinical trials are warranted.

Administration, Oral↗
PubMed1996

Recurrence of a choroidal neovascular membrane in a patient with punctate inner choroidopathy treated with daily doses of thalidomide.

PURPOSE: To determine whether thalidomide therapy can prevent a recurrence of a choroidal neovascular membrane in a patient with punctate inner choroidopathy. METHODS: Case report. In a 38-year-old woman with bilateral punctate inner choroidopathy, thalidomide therapy was initiated three days after laser photocoagulation of a choroidal neovascular membrane. RESULTS: The patient had a recurrence of the choroidal neovascular membrane eight months after the start of thalidomide therapy. CONCLUSIONS: The failure of thalidomide to prevent a recurrence of a choroidal neovascular membrane in this patient suggests that this medication may have only a limited benefit in preventing recurrences of choroidal neovascular membranes.

Adult↗
PubMed1999

Thalidomide therapy for patients with refractory Crohn's disease: an open-label trial.

BACKGROUND & AIMS: Inhibition of tumor necrosis factor is a proposed mechanism for the anti-inflammatory properties of thalidomide. We performed an open-label trial of thalidomide in refractory Crohn's disease. METHODS: Twenty-two patients with refractory Crohn's disease (Crohn's Disease Activity Index [CDAI] > 200 and/or draining perianal disease) initiated therapy with thalidomide, 200 mg at bedtime (18 patients), or 300 mg at bedtime (4 patients). CDAI and goal interval scores (GIS) were assessed at weeks 0, 4, and 12. Clinical response for patients with luminal disease was defined as reduction in CDAI score of >150 points and for fistula patients was 2 scores of >/=1+ in 3 parameters of the GIS. Clinical remission was defined as a total CDAI < 150 (luminal patients) or >/=2+ for all parameters of the GIS (fistula patients). RESULTS: Nine patients with luminal disease and 13 with fistulas (16 male, 6 female) were enrolled. The median CDAI score at entry was 371 (95-468). Sixteen patients completed 4 weeks of treatment (12 clinical responses, 4 clinical remissions). All 14 patients completing 12 weeks met criteria for clinical response. Nine achieved clinical remission (3 luminal, 6 fistula patients). The median CDAI score was 175 (30-468; P < 0.001 vs. baseline). CONCLUSIONS: Thalidomide is efficacious in some patients with refractory Crohn's disease.

Adult↗
PubMed2001

Therapeutic dilemmas with thalidomide in multiple myeloma: case discussions.

Three cases of multiple myeloma treated with thalidomide are presented which highlight therapeutic dilemmas presented by therapy with this new agent. The difficulty of stem cell collection during thalidomide therapy is illustrated. The question of continuation of thalidomide after attainment of a plateau or remission is discussed and the management of neuropathy considered. Thalidomide, being a novel drug, presents a number of therapeutic issues that have yet to be resolved.

Adult↗
PubMed2002

Thalidomide in the treatment of myelodysplastic syndrome with fibrosis.

A 67-year-old woman was admitted for investigation of pancytopenia. Bone marrow biopsy was compatible with myelodysplastic syndrome (MDS) with fibrosis. For the next 20 months the patient received transfusions of packed red cells, while a 3-month-trial of erythropoetin was unsuccesful. She was then treated with thalidomide 400mg per day. During the next months, a gradual rise in Hb value was noticed and the patient eventually became transfusion independent. Repeat bone marrow biopsy revealed a significant decrease on the degree of fibrosis. Thalidomide has shown excellent results in the treatment of multiple myeloma probably due to its anti-angiogenic activity. It is possible that in our patient thalidomide acted as an anti-fibrotic agent. It will be very interesting to test this novel activity of thalidomide in a large number of patients.

Aged↗
PubMed1984

Studies on the anti-inflammatory properties of thalidomide: effects on polymorphonuclear leukocytes and monocytes.

The effects of thalidomide on polymorphonuclear leukocyte (PMN) and monocyte function were studied in vitro. Phagocytosis of latex beads by both PMNs and adherent monocytes was significantly depressed (p less than 0.01) after a 1-hour incubation of cells with 10 microgram/ml of thalidomide. Concentrations of 1 microgram/ml stimulated monocyte phagocytosis (p less than 0.01) but did not influence PMNs. Incubation of monocytes with 10 micrograms/ml resulted in a significant reduction of chemiluminescence (CL) but had no effect at 1 microgram/ml concentrations. There was no significant action on PMN CL at either concentration. Finally, 10 micrograms/ml concentrations of thalidomide were not cytotoxic for either cell type after 18-hour incubations. In conclusion, the results of these studies may at least partially explain the efficacy of thalidomide in some inflammatory conditions.

Adult↗
PubMed1996

Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses.

Thalidomide, a hypnosedative drug introduced in the 1950s, has been used in a variety of dermatologic conditions during the past few decades. Although originally withdrawn from the world market on discovery of its teratogenic effect, it has since been selectively reintroduced for use in various disorders thought to have an autoimmune or inflammatory basis. A review of the literature focused on clinical uses of thalidomide in the treatment of dermatologic diseases was performed. Diseases for which thalidomide has been found effective include erythema nodosum leprosum, prurigo nodularis, actinic prurigo, discoid lupus erythematosus, aphthous stomatitis, Behçet's syndrome, and graft-versus-host disease. Side effects such as teratogenicity and peripheral neuropathy remain its limiting factor. Thalidomide is a useful addition to the therapeutic armamentarium for treatment-resistant dermatoses as long as proper vigilance for adverse effects is maintained.

Humans↗
PubMed2002

[Lung toxicity due to thalidomide].

Although the side effects of thalidomide are well known, lung toxicity has not been reported. We describe the case of a 65-year-old man with multiple myeloma (IgG kappa) in stage IA who, on the thirty-seventh day of treatment with thalidomide, developed acute coughing, general malaise, dyspnea at rest and sudoresis. Blood pressure was 90/60 mm Hg and temperature was normal. An interstitial and alveolar pattern was visible on the right side of a chest film and arterial blood gases indicated partial respiratory insufficiency (pH 7.40, PaCO2 40 mmHg, PaO2 47 mmHg). Blood analysis showed alterations expected for multiple myeloma and microbiology was negative (sputum and blood cultures and urinary antigen detection for Streptococcus pneumoniae and Legionella pneumophila). After thalidomide was withdrawn and oxygen and intravenous corticoids were administered, outcome was good. A chest film 4 days later was normal and arterial blood gases showed that respiratory insufficiency had disappeared. We conclude that severe lung toxicity should be included among the potential adverse effects of thalidomide.

Aged↗
PubMed1998

The effect of thalidomide treatment on vascular pathology and hyperalgesia caused by chronic constriction injury of rat nerve.

Tumor necrosis factor alpha (TNF) may be involved in the pathogenic mechanisms of neuropathic pain by affecting endothelial cells and by upregulation of receptor sensitivity in afferent nerve fibers. To test the hypothesis that TNF plays a role in the vascular changes and the pain-related behavior in an experimental painful neuropathy in rats produced by tying loosely constrictive ligatures around one sciatic nerve, we investigated the effect of thalidomide, a selective blocker of TNF-production in activated macrophages. In rats in which treatment with thalidomide was started preoperatively, there was diminished mechanical allodynia and thermal hyperalgesia during the early stage of the disease. TNF immunohistochemistry revealed reduced endoneurial immunoreactivity on day 5 post surgery as compared to sham-treated animals. The pathologic vascular changes were also reduced in thalidomide-treated rats. Starting treatment with thalidomide at a time point when hyperalgesia was already present did not alter the course of the pain-related behavior. We conclude that preemptive treatment with a substance that blocks production of TNF reduces pain-related symptoms and pathologic vascular changes in the chronic constriction injury model of neuropathic pain.

Analysis of Variance↗
PubMed1999

Quantitative determination of thalidomide in human serum with high-performance liquid chromatography using protein precipitation with trichloroacetic acid and ultraviolet detection.

A validated and precise reversed-phase high-performance liquid chromatographic method for the determination of thalidomide in serum, with phenacetin as an internal standard, is described. Protein precipitation, using trichloroacetic acid, was used for clean-up. The aliquot was chromatographed on a octadecyl column, using an eluent composed of 250 ml 0.01 M potassium dihydrogenphosphate, adjusted to a pH of 3.0 with a 43% phosphoric acid solution, mixed with 750 ml methanol. Ultraviolet detection was used at an operation wavelength of 220 nm. Hydrolytic degradation was prevented during analysis by acidification of samples with the precipitation reagent. Thalidomide and phenacetin were found to have retention times of 7.9 and 15.0 min, respectively. Recoveries ranging from 79 to 84% were found for both components, with reproducibility relative standard deviations of 0.8-3% and repeatability coefficients of 1.2-3%. A mean correlation coefficient of 0.9995 was found for the linear calibration curve (n=2) of thalidomide with limits of quantitation of 0.222-21 mg/l. The method appeared to be feasible for pharmacokinetic studies with thalidomide.

Blood Proteins↗
PubMed1995

Effect of thalidomide on the inflammatory response in cerebrospinal fluid in experimental bacterial meningitis.

In experimental bacterial meningitis in rabbits, the inflammatory process is largely mediated by cytokines such as IL-1 and TNF-alpha. Since thalidomide has been shown to inhibit TNF-alpha production, experiments were carried out to determine whether the drug can modulate the inflammatory response to either lysates of H. influenzae (gram negative) or heat killed S. pneumoniae (gram positive) in rabbits. The introduction of a lysate of H. influenzae into the CSF of rabbits causes a very acute inflammatory response, as indicated by a rapid increase in TNF-alpha levels in the CSF and a concomitantly rapid leukocytosis. In contrast, the introduction of heat killed S. pneumoniae, induces a more indolent inflammatory response which also wanes more slowly. Thalidomide treatment reduces TNF-alpha production in both experimental systems, but has a greater effect on the more indolent gram positive inflammatory response in which peak TNF-alpha levels in the CSF are reduced by > 50%. Also, a sustained inhibition of leukocytosis is observed in the inflammatory response to heat-killed gram positive bacteria. In meningeal inflammation induced by the Gram negative lysate, treatment with thalidomide results in only a 29% inhibition of TNF-alpha release into the CSF. In contrast to the drug effect on TNF-alpha, thalidomide treatment does not significantly affect IL-1 levels in these models of rabbit bacterial meningitis.

Animals↗
PubMed2003

Alpha-fluoro-substituted thalidomide analogues.

Thalidomide, (1), has made a remarkable comeback from its days of a sedative with teratogenic properties due to its ability to selectively inhibit TNF-alpha, a key pro-inflammatory cytokine and its clinical benefit in the treatment of cancer. Thalidomide contains one chiral center and is known to be chirally unstable under in vitro and in vivo conditions. It has been hypothesized that different biological properties are associated with each isomer. Thus, chirally stable analogues of thalidomide, alpha-fluorothalidomide, (3) and alpha-fluoro-4-aminothalidomide (4) were prepared by electrophilic fluorination. Analogue 3 was found to be cytotoxic and did not inhibit TNF-alpha production in LPS stimulated hPBMC below toxic concentrations. On the other hand, 4 was non-cytotoxic at the tested concentrations and was found to be 830-fold more potent than thalidomide as TNF-alpha inhibitor.

Cells, Cultured↗
PubMed2002

Structural development of biological response modifiers based on thalidomide.

Thalidomide (N-alpha-phthalimidoglutarimide) is a teratogenic hypnotic/sedative agent which was used widely in the late 1950s and the early 1960s. In spite of its withdrawal from the market because of its severe teratogenicity, there has been a resurgence of interest in the drug in recent years due to its potential usefulness for the treatment of various diseases, including acquired immunodeficiency syndrome (AIDS) and various cancers. It has been revealed that thalidomide elicits pleiotropic effects and is a multi-target drug. Our structural development studies of thalidomide, focusing on tumor necrosis factor-alpha(TNF-alpha) production-regulating activity, anti-androgenic activity, puromycin-sensitive aminopeptidase-inhibiting activity, alpha-glucosidase-inhibiting activity, and inhibitory activities toward some other enzymes, are reviewed in relation to the pharmacological effects of thalidomide.

Androgen Antagonists↗
PubMed2002

In vitro biotransformation of (R)- and (S)-thalidomide: application of circular dichroism spectroscopy to the stereochemical characterization of the hydroxylated metabolites.

Circular dichroism (CD) spectroscopy was successfully used for the stereochemical characterization of the hydroxylated metabolites formed during the in vitro biotransformation of (R)- and (S)-thalidomide. Incubation extracts of the individual enantiomers were analyzed by HPLC on an achiral stationary phase combined with CD detection. The CD data of the almost enantiopure eluates of the metabolites were compared with the CD spectra quantum chemically calculated for the respective structures. The results allowed us a reliable determination of the absolute stereostructure for all of the metabolites. The chiral center of thalidomide is unaffected by the stereoselective biotransformation process. (3'R,5'R)-trans-5'-hydroxythalidomide is the main metabolite of (R)-thalidomide, which epimerizes spontaneously to give the more stable (3'S,5'R)-cis isomer. On the contrary, (S)-thalidomide is preferentially metabolized by hydroxylation in the phthalimide moiety, resulting in the formation of (S)-5-hydroxythalidomide.

Animals↗
PubMed2001

Differential effects of thalidomide on angiogenesis and tumor growth in mice.

Thalidomide, clinically used as an antiinflammatory and antitumoral drug, inhibited sponge-induced angiogenesis when administered systemically (100 mg/kg(-1)) in mice. However, it failed to inhibit solid Ehrlich tumor in the same mouse strain. We have used functional, biochemical and histological parameters to assess neovascularization and fibrovascular tissue infiltration of the mice sponge granuloma. The neovascularization growth as detected by development of blood flow and hemoglobin content extracted from the implants showed that thalidomide inhibited fibrovascular tissue formation by 40%. The functional and biochemical parameters correlated well with the histological study. Thalidomide had no inhibitory effect in the development of Ehrlich tumor. The detection of this selective action using the same animal strain bearing two different processes, supports the hypothesis that rather than species specificity, thalidomide is tissue specific. This approach may be used to identify the specificity of other therapeutic agents against distinct angiogenesis-dependent diseases.

Angiogenesis Inhibitors↗
PubMed2001

Potent inhibition of cytokine production from intestinal lamina propria T cells by phosphodiesterase-4 inhibitory thalidomide analogues.

In Crohn's disease, intestinal lamina propria (LP) T cells overproduce TNF-alpha and IFN-gamma, and clinical and animal studies indicate that this is pathogenic. Thalidomide influences cytokine production by leukocytes, inhibiting macrophage TNF-alpha, and is beneficial in treating Crohn's disease. Chemical analogues have been synthesized that may lack teratogenic and other side effects of thalidomide. We tested three analogues [selective cytokine inhibitory drugs (SelCIDs) A, B, and C, all potent PDE4 inhibitors] for effect on TNF-alpha, IFN-gamma, and IL-10 production by and on proliferation of intestinal LP mononuclear cells after T-cell stimulation and results were compared with those for peripheral blood leukocytes (PBL). While thalidomide itself had little effect, the SelCIDs were potent inhibitors, with relative inhibitory potencies: A> or =B>>C. The LP T cells were less sensitive to inhibition by the SelCIDs than were PBL. Since highly pre-activated PBL were even less sensitive, activation state alone can account for the responsiveness of intestinal LP T cells. Thalidomide analogues could play a role in treating Crohn's disease and other inflammatory disorders.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Phase II study of thalidomide in the treatment of recurrent glioblastoma multiforme.

Treatment options and prognosis remains poor for patients with recurrent glioblastoma multiforme. These tumors are highly vascularised and over express angiogenic factors such as vascular endothelial growth factor and may potentially be responsive to antiangiogenic therapies. We present the results of a phase II trial of Thalidomide, an antiangiogenic agent, in the treatment of recurrent glioblastoma multiforme. Patients were treated with 100 mg/day of Thalidomide, increased at weekly intervals by 100 mg to a maximum tolerated dose of 500 mg/d. Forty-two patients were enrolled, with 38 patients being assessable for response and 39 for toxicity. Two patients (5%) achieved a partial response and 16 (42%) had stable disease. The median survival was 31 weeks and the 1-year survival was 35%. Patients who had a partial response or stable disease had either a stabilisation or improvement in quality of life scores or performance status. Overall Thalidomide was well tolerated with no grade 4 toxicities and no treatment related deaths. The median maximum tolerated dose was 300 mg/day. The most common toxicity was fatigue to which patients developed tachyphylaxis. There was no correlation demonstrated with plasma vascular endothelial growth factor levels and response or survival. Thalidomide is a well-tolerated drug that may have some activity in the treatment of recurrent glioblastoma. Optimum dosing with antiangiogenic agents is currently under investigation. Chronic low dose therapy may be required to see conventional responses or improvements in time to progression. The dose required to achieve optimal biological impact may be better defined once we have established reliable surrogate endpoints.

Adult↗
PubMed2002

Percutaneous delivery of thalidomide and its N-alkyl analogs.

PURPOSE: The purpose of this study was to determine the permeation parameters of thalidomide and three of its N-alkyl analogs and to establish a correlation between the physicochemical properties of these compounds and their percutaneous rates of absorption. METHODS: In vitro permeation studies were performed from buffer, n-alkanols and various mixed components using vertical Franz diffusion cells fitted with human epidermal membranes. RESULTS: Measured steady-state fluxes indicate that N-methyl thalidomide is a far better penetrant of human skin than the "parent molecule". However, fluxes through skin drop off markedly from that of the methylated compound when the chain length is extended to propyl and pentyl. However, they remain well above the flux of thalidomide, which is less than 0.025 microg/cm2/h. CONCLUSIONS: The best skin permeant of this series was the N-methyl analog, which also exhibited the highest water (buffer) solubility compared to thalidomide, and the N-propyl and N-pentyl analogs. The N-propyl and N-pentyl analogs were more lipid soluble and exhibited higher partition coefficient values than the N-methyl analog. From all the permeability data using buffer, a series of n-alkanols and various combinations of solvents and enhancers as vehicles, the more water-soluble compound and not the more lipid soluble one was the best skin permeant.

Administration, Cutaneous↗