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PubMed2001

Enantioseparation of aminoglutethimide and thalidomide by high performance liquid chromatography or supercritical fluid chromatography on mono-2 and mono-6-O-pentenyl-beta-cyclodextrin-based chiral stationary phases.

Mono-2 and mono-6-O-pentenyl-beta-cyclodextrin (mono-2-pent-beta-CD and mono-6-pent-beta-CD), covalently linked to mercaptopropylsilica gel (thiol-Si) through thioether or sulfone linkage, reveal differentiated enantioselectivities in the separation of piperidine-2,6-dione-related drugs, namely aminoglutethimide and thalidomide, in supercritical fluid conditions. Supercritical fluid chromatographic resolution on completely defined mono-cyclodextrin derivative-based chiral stationary phases (CSP) is a method of choice for the separation of aminoglutethimide but not effective for thalidomide. For both high performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) conditions, the impact of the position, imposed to be 2 or 6 in our synthetic pathway, of the pentenyl moiety on one of the glucopyranosidics of the CD cage is of crucial importance in the chiral discrimination phenomenon. Additionally, the nature of the heteroatom present in the spacer arm between the CD and the silica gel, in this case thioether or sulfone functionality, is also essential for the chiral recognition mechanism(s) for the solute enantiomer.

Aminoglutethimide↗
PubMed2004

Chiral discrimination between thalidomide enantiomers using a solid surface with two-dimensional chirality.

Chiral discrimination between thalidomide enantiomers was achieved using the self-assembled monolayer (SAM) of an atropisomeric compound, 1,1'-binaphthalene-2,2'-dithiol (BNSH), which takes a two-dimensional chiral arrangement on gold(111) surface. Interestingly, an "all-or-none" type enantioselectivity appears; one enantiomeric form of BNSH SAM allows the adsorption of only one enantiomer of thalidomide. In addition, the response of a racemic SAM of BNSH was revealed to be one-half of that caused by pure enantiomeric SAM.

Carboxylic Acids↗
PubMed2006

Phase II study of temozolomide and thalidomide in patients with metastatic melanoma in the brain: high rate of thromboembolic events (CALGB 500102).

BACKGROUND: Preliminary studies suggesting that extended-dose temozolomide with thalidomide is safe and active in patients with metastatic melanoma have led to frequent use of this oral regimen. To confirm these observations the combination was tested in a multicenter Phase II trial in patients with melanoma brain metastases. METHODS: Eligible patients had melanoma brain metastases, with or without systemic metastases. The primary endpoint was response rate in brain metastases. Patients received temozolomide at a dose of 75 mg/m2/day for 6 weeks with a 2-week rest between cycles, and thalidomide (escalated to 400 mg/day for patients age < 70 years or to 200 mg/day for patients age > or = 70 years). A 2-stage design required > or = 3 responses in the first 21 patients before enrolling 29 additional patients in the second stage. RESULTS: Sixteen eligible patients were enrolled. No objective responses were observed. The median survival was 23.9 weeks. Seven patients withdrew because of tumor progression; 7 were removed during Cycle 1 because of adverse events, including allergic reaction (1 patient), severe fatigue (1 patient), sudden death (1 patient), and thromboembolic events (pulmonary embolism in 3 patients and deep vein thrombosis in 1 patient); 2 patients withdrew when the study was suspended and subsequently closed. No associations could be established between baseline characteristics and toxicity. CONCLUSIONS: The proportion of patients with lethal or potentially life-threatening adverse events was high (0.31, 95% confidence interval, 0.11-0.59), and the absence of objective responses made it unlikely that further accrual would demonstrate the efficacy of the regimen. These observations provide little support for the use of this combination for melanoma brain metastases unless safe and effective methods to prevent thrombosis are developed.

Adult↗
PubMed2004

The combination of intermediate doses of thalidomide and dexamethasone reduces bone marrow micro-vessel density but not serum levels of angiogenic cytokines in patients with refractory/relapsed multiple myeloma.

The aim of the study was the evaluation of anti-angiogenic activity of the combination of intermediate doses of thalidomide and dexamethasone in patients with refractory/relapsed myeloma. Twenty-five patients were included in the study. Microvessel density (MVD) was evaluated in marrow biopsies before and after treatment. Serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), tumor necrosis factor-alpha (TNF-alpha), which have angiogenic potential and interleukin-6 (IL-6), IL-1beta, soluble IL-6 receptor (sIL-6R), and transforming growth factor-beta (TGF-beta) which are involved in the disease biology, were measured before treatment and then every 2 weeks for 8 weeks. Pretreatment levels of MVD, VEGF, b-FGF, IL-6, sIL-6R were increased in the patients compared to controls. The overall response rate to therapy was 72%. The administration of the combined regimen produced a significant reduction in MVD in responders. However, an increase in serum levels of VEGF, b-FGF, IL-6, sIL-6R was observed post-treatment in responders. In contrast, serum levels of TNF-alpha, TGF-beta, IL-1beta did not differ between patients and controls and remained unchanged during the study. These results suggest that the combination of thalidomide plus dexamethasone is an effective treatment for myeloma reducing MVD marrow levels but not serum levels of angiogenic cytokines or cytokines implicated in myeloma biology.

Aged↗
PubMedDate not supplied

Thalidomide neuropathy: an electrophysiologic study.

Thalidomide is effective in the treatment of such disabling dermatologic diseases as aphthosis, discoid lupus erythematosus, and prurigo nodularis, in which other drugs fail. However, its use can induce neuropathy necessitating caution in its administration. It was found in this electrophysiologic study of 13 patients that the data best revealing neuropathy, even when clinical abnormalities were not apparent, were reduction of sensory nerve action potential amplitude on the sural nerve, increase of somatosensory evoked potential latency following sural nerve stimulation, and reduction of sensory action potential amplitude on stimulating the median nerve at the wrist. In two patients, electrophysiologic abnormalities had increased after withdrawal, suggesting a prolonged action of thalidomide. Timely reduction of dosage, after detection of changes indicating the onset of side effects, could reduce the risk of the sometimes rapid emergence of clinical symptoms.

Action Potentials↗
PubMed1987

Prenatal diagnosis of thalidomide syndrome.

A case of thalidomide syndrome diagnosed by ultrasound in the 17th week of pregnancy is presented. The pregnant woman had leprosy and received adjuvant treatment with thalidomide. The affected fetus was exposed to the drug until the 35th day of pregnancy and presented absent external ears, upper limb phocomelia and absent tibiae and fibulae. No internal organ abnormalities were noticed at autopsy.

Abnormalities, Drug-Induced↗
PubMed1978

Developmental staging and thalidomide teratogenicity in the green monkey (Cercopithecus aethiops).

The developmental stages of 11 Cercopithecus aethiops embryos, 24 to 45 days post-mating, are described. The onset of organogenesis in this species is approximately five to seven days later than that reported for macaques and baboons. This temporal difference in the embryonic period is an important factor in the analysis of the subsequent teratogenic study. Oral administration of thalidomide in single or multiple (3-day) treatment periods to pregnant green monkeys between days 28 and 33 resulted in defects of the limbs which resemble those observed in macaques and baboons. However, the sensitive period occurs approximately four days later than that reported for another nonhuman primates. These results indicate that the sensitive period of the limbs to thalidomide coincides with their earliest development.

Abnormalities, Drug-Induced↗
PubMed1981

Fetal ear malformations induced by maternal ingestion of thalidomide in the bonnet monkey (Macaca radiata).

Gross malformations of the external, middle, and internal ear were seen in fetal monkeys following maternal ingestion of thalidomide. Twenty-five pregnant bonnet monkeys (Macaca radiata) were each given a single oral dose of 10 mg/kg of thalidomide on day 24, 25, 26, 27, 28, or 29, or 30 mg/kg on day 25 or 28 of gestation. (Day of mating is assumed to be day zero of pregnancy). The skeletons, processed and stained with Alizarin Red S, were examined for changes in configuration and/or ossification of the ossicles and temporal bones. Bilateral temporal bones of one case, treated on day 24, were sectioned at 10 microns and examined histologically. Twelve fetuses collected at 70 +/- 3 days of gestation showed no gross ear defects, while 10 out of 13 fetuses collected at 100 +/- 3 days of gestation had structural anomalies similar to those observed in humans. All malformations were severe in fetuses treated on day 24 of gestation and lessened in degree of severity with treatments on days 25-28. Fetuses treated on day 29 were normal. External ear anomalies included microtia with meatal atresia or stenosis, and varying degrees of auricular hypoplasia. Defects of the middle ear were predominantly hypoplasia of malleus, incus, and tympanic ring. Fused ossicles and cochlear and vestibular window abnormalities were only seen in animals treated on day 24. The internal ear exhibited petrosal hypoplasia and delayed ossification of the lateral aspect of the lateral and posterior semicircular canals. Cochlear, vestibular, semicircular, and transcapsular canal defects were confirmed histologically in one case.

Abnormalities, Drug-Induced↗
PubMed1996

Inducer-specific bidirectional regulation by thalidomide and phenylphthalimides of tumor necrosis factor-alpha production.

Regulation by thalidomide [N(alpha)-phthalimidoglutarimide] of tumor necrosis factor (TNF)-alpha production was found to be inducer-specific. Thalidomide enhances TNF-alpha production by human leukemia HL-60 cells induced with 12-O-tetradecanoylphorbol 13-acetate (TPA), while it inhibits TNF-alpha production induced with okadaic acid (OA) in the same cell line. Some phthalimide analogs, included PP-33 [2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione] and its 4,5,6,7-tetrafluora derivative FPP-33), also showed such an inducer-specific bidirectional TNF-alpha production-regulating activity. The structure-activity relationships of the compounds tested are similar, but not identical, in the TPA-stimulated HL-60 and OA-stimulated HL-60 assay systems.

Carcinogens↗
PubMed1988

Embryotoxic effects of thalidomide-derivatives in the non-human primate Callithrix jacchus. I. Effects of 3-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine (EM12) on skeletal development.

The response of pregnant marmosets (Callithrix jacchus) to the thalidomide derivative EM 12 was evaluated. EM 12 was selected for these studies because it is more active than thalidomide and is much more stable for hydrolysis. Skeletal gross structural abnormalities were observed when EM 12 was given to marmosets for 3-7 days during the period between days 49 and 60 post ovulation. Using the treatment schedule finally adapted in our laboratory, i.e. treatment during days 51-57 post ovulation, doses of 5 (or 10) mg EM 12/kg body wt induced the typical limb abnormalities known from man with an 80-100% certainty. In some animals we could observe the typical pattern of abnormalities even with doses as low as 1 mg EM 12/kg body wt. Abnormalities of the skeleton induced during this sensitive period are described. None of these (except some bifurcations of ribs) were seen in any of the ten litters (23 fetuses) serving as controls during the period of the study.

Abnormalities, Drug-Induced↗
PubMed1988

The enantiomers of the teratogenic thalidomide analogue EM 12: 1. Chiral inversion and plasma pharmacokinetics in the marmoset monkey.

The plasma pharmacokinetics of the enantiomers of 2-(2,6-dioxopiperidine-3-yl)-phthalimidine (EM 12) and the racemic mixture of this substance were investigated in Callithrix jacchus, a thalidomide-sensitive primate. Single doses of 5 mg/kg body wt were administered orally or intraperitoneally. Maximum plasma concentrations were reached 1 h after administration of the enantiomers, and 3 h after application of the racemate. The mean plasma elimination half-life was in the range of 5 h for the enantiomers, as well as for the racemic mixture, although there was a tendency toward slower elimination and higher plasma AUC values of the S-enantiomer: thus, after administration of the (greater than 99%) pure enantiomers, the plasma AUC value of the administered S-enantiomer was found to be more than one-third higher than that of the administered R-enantiomer. Racemisation of the R- and the S-form of EM 12 occurred both in vitro (phosphate buffer, pH 7.4, 37 degrees C) and in vivo. The maximum plasma concentrations of the antipodes produced via chiral inversion were between 13% and 21%; the plasma AUC values of the resulting antipodes were between 24% and 30% of the corresponding values of total EM 12. The plasma pharmacokinetic data, including the extent of the chiral inversion obtained after p.o. and i.p. application of the substances, were in the same range. The results indicate that both enantiomers racemise with appreciable rates; this may be expected to complicate the interpretation of studies designed to evaluate stereoselective differences with respect to teratological activities of EM 12 and related substances such as thalidomide.

Animals↗
PubMed1988

Embryotoxic effects of thalidomide derivatives on the non-human primate Callithrix jacchus; 3. Teratogenic potency of the EM 12 enantiomers.

The teratogenic potencies of the enantiomers of 2-(2,6-dioxopiperidine-3-yl)-phthalimidine ( = EM 12), a teratogenic thalidomide analogue, were investigated in Callithrix jacchus, a primate very sensitive to the teratogenic action of this thalidomide analogue. The results indicate that the S-(-)-form of EM 12 is clearly more teratogenic than the R-(+)-form. The interpretation of the studies designed to evaluate stereo-selective differences in the teratogenicity of the enantiomers becomes difficult, since both enantiomers racemise in vivo with appreciable rates (Schmahl et al. 1988a, b). Therefore, it cannot be concluded as yet that the R-(+)-form lacks all teratogenic potential.

Abnormalities, Drug-Induced↗
PubMed1977

[Unmyelinated nerve fibers in senile nerves and in late thalidomide neuropathy: a quantitative electron microscopic study (author's transl)].

Sural nerve biopsies of four patients, aged 54--76 years, with a predominantly sensory type of neuropathy following high dosages of thalidomide were examined by light and electron microscopy. The present study includes a qualitative and quantitative evaluation of unmyelinated nerve fibers. Despite severe neuropathy, increased numbers of small unmyelinated axons per endoneurial area were noted in all patients. This numerical increase appeared to be independent of aging, since it was not seen in two senile controls, studied at the age of 83 and 88 years. The increase in the endoneurial density of unmyelinated axons, especially of small sized fibers, is likely to be related to regeneration following degeneration of unmyelinated axons although endoneurial shrinkage secondary to loss of large myelinated fibers could have caused an additional increase in the number of axons per endoneurial area. Axonal sprouting, despite degeneration of large numbers of myelinated and unmyelinated fibers, appears to be consistent with some of the characteristic clinical features of thalidomide neuropathy such as paresthesias, hyperesthesia for pain and temperature, and disturbances of autonomic functions. On the other hand, a variable number of empty Schwann cells (bands of Büngner) and pockets at the surface of many Schwann cells noted in the four patients with neuropathy were also seen in both senile controls with no signs of neuropathy. Thus, it is obvious that pockets and empty Schwann cells may be related to aging or other causes of slow axonal wasting with Schwann cell proliferation and are not necessarily associated with clinically manifest neuropathy.

Aged↗
PubMed1995

[Successful treatment of a case of cutaneous Langerhans cell granulomatosis with 2-chlorodeoxyadenosine and thalidomide].

We describe the case of a 65-year-old female patient with cutaneous Langerhans' cell granulomatosis without any signs of disease in other organs. She also had systemic lupus erythematosus that had been diagnosed several years before. The coexistence of these two diseases has not been described before as far as we know. The purine analogue 2-chlorodeoxyadenosine (Cladribin), which has been used successfully in the treatment of hairy cell leukaemia, induced complete remission in our patient after 1 week of treatment. After 2 months, however, the patient had a relapse; this was successfully treated with thalidomide. A new understanding of Langerhans' cells granulomatosis as a reactive but not cancerous disease has emerged as a result of recent investigations showing that tumour necrosis factor-alpha (TNF-alpha) plays an important part in the induction of Langerhans' cells from their immature precursors. Because thalidomide has been shown to inhibit TNF-alpha production, down-modulation of this cytokine seems to be a useful treatment strategy in Langerhans' cell granulomatosis. Some asspects of the diagnosis and therapy of this disease are briefly reviewed.

Aged↗
PubMed2002

[Thalidomide therapy of cutaneous lupus erythematosus].

Immunosuppressive and immune-modulating substances such as corticosteroids, chloroquin, hydroxychloroquin, azathioprin, methotrexate, and others are standards in therapy of cutaneous lupus erythematosus. However, alternative substances are necessary when standard therapy regimens fail or are associated with side effects. Describing the course of disease in five female patients, we demonstrate alternative treatment of subacute cutaneous lupus erythematosus with thalidomide, showing good symptom response and possible side effects. By careful patient selection, we observed no polyneuropathy as it is most commonly described. In two cases, maculopapulous exanthema induced by medication was seen. The teratogeny of the substance must be taken into account in prescription. In selected cases, thalidomide can be a highly effective therapeutic option in the treatment of subacute cutaneous lupus erythematosus.

Adult↗
PubMed2001

[Chemotherapy-induced erythema nodosum leprosum: successful treatment with thalidomide].

The severity and outcome of a chronic granulomatous infection caused by M. leprae depend on the cell-mediated immunity towards the pathogen. The disease classification is based on the host's response to M. leprae ranging from high to low resistance (polar tuberculoid leprosy to polar lepromatous leprosy). The host's position in the spectrum is not stable; leprosy reactions reflecting changed immune status may occur spontaneously or during chemotherapy. The type II reaction or erythema nodosum leprosum can most often be seen in patients with lepromatous leprosy, a multiorgan disease characterized by an unrestricted bacillary replication. Clinically, this reaction is characterized by crops of painful bright pink, dermal and subcutaneous nodules arising in clinically normal skin, in association with fever, malaise, glomerulonephritis and arthralgias. Therefore, prompt institution of immunosuppressive therapy with corticosteroids or thalidomide is recommended. This case report describes the development of erythema nodosum leprosum during chemotherapy treated successfully with thalidomide. Furthermore, immunologic effects and potential side effects of this drug are discussed.

Adult↗
PubMed2004

Use-dependent cortical plasticity in thalidomide-induced upper extremity dysplasia: evidence from somaesthesia and neuroimaging.

In this study cerebral reorganization was investigated in thalidomide-damaged subjects who use their feet to compensate for their malformed upper extremities. Tactile localization across toes was combined with fMRI to study use-dependent plasticity of the human somatosensory cortex. The manner of compensatory foot use was assessed by a questionnaire. In the behavioural experiment toes were stimulated with above threshold monofilaments and subjects had to report which toe was stimulated. When feet were employed for all everyday actions subjects made significantly fewer errors in the localization task. In subjects who use their feet only for specific actions such as grasping objects there were as many localization errors as in the control group of thalidomide-affected subjects with normal extremities. However, the patterns of mislocalizations were different with less errors occurring for the toe of the dominant foot involved in these actions. Functional MRI showed stronger haemodynamic responses to electrical stimulation of the toes in subjects using their feet for everyday actions as compared to controls. Our data show that long-term use of the feet for fine sensorimotor skills leads to better performance in tactile localization and changes in cerebral SI representation supporting the notion of use-dependent plasticity in the somatosensory cortex.

Activities of Daily Living↗
PubMed2004

Modification of thrombomodulin plasma levels in refractory myeloma patients during treatment with thalidomide and dexamethasone.

Deep venous thrombosis (DVT) has been variably reported in multiple myeloma patients during treatment with thalidomide alone or in combination with chemotherapy or dexamethasone. With the aim of investigating this complication, we performed, on a cohort of 13 relapsed refractory MM patients treated with low-dose thalidomide (100 mg/day) and dexamethasone (20 mg p.o./day for 4 days every 2 weeks), a serial evaluation of different laboratory parameters implicated in DVT. No significant abnormalities in all genetic, serologic, or plasmatic parameters studied were registered, apart from thrombomodulin which showed significant variations between baseline and 1st-month values and 1st- and 3rd-month values. In conclusion, the evidence of significant variations of thrombomodulin values in the 1st month of therapy, which is considered to involve the highest risk of thrombosis, might support a role for thrombomodulin in this complex mechanism.

Adult↗