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1.
Ophthalmic Res ; 35(3): 143-9, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12711841

RESUMO

CG5601 is a novel immunomodulatory substance showing anti-inflammatory properties comparable to thalidomide. To investigate the anti-inflammatory effects of CG5601 in endotoxin-induced uveitis (EIU) and to evaluate its influence on leukocyte-endothelium interaction, the anterior chamber inflammatory reaction was assessed and intravital fluorescence microscopy was carried out at 2, 4, 8 and 24 h. Lewis rats received an intraperitoneal injection of CG5601 (200 mg/kg b.w.) at the time of lipopolysaccharide injection. At 8 and 24 h, CG5601 inhibited the cell migration and protein concentration in the aqueous humor compared to untreated EIU (p < 0.0001). There was no significant difference between nontreated animals and vehicle controls. The treatment of CG5601 reduced the number of rolling leukocytes. At early time points (2 and 4 h), inhibition of rolling leukocyte flux was significant (p < 0.005). The rise of serum TNF-alpha levels in EIU at 2 h was reduced. CG5601 exerts potent anti-inflammatory effects in EIU.


Assuntos
Anti-Inflamatórios/uso terapêutico , Uveíte/tratamento farmacológico , Animais , Humor Aquoso/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Endotoxinas , Feminino , Imidazóis/uso terapêutico , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Ratos , Ratos Wistar , Compostos de Espiro/uso terapêutico , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Tiazóis/uso terapêutico , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo , Uveíte/induzido quimicamente
2.
Bioorg Med Chem ; 9(5): 1279-91, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11377186

RESUMO

A series of new water-soluble thalidomide prodrugs was prepared. All compounds were derivatized on the nitrogen of the glutarimide ring. Esters of natural amino acids and succinic acid derivatives have been introduced by reaction with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were prepared from halomethyl derivatives. Additionally, a methoxymethyl derivative and a carboxymethyl derivative were prepared directly from thalidomide. Most compounds showed a very large increase in water solubility compared to thalidomide itself (0.012mg/mL). The amorphous hydrochlorides of the N-methylalanine ester 8, valine ester 9, and glycylglycine ester 10, respectively, were the most soluble compounds showing solubility greater than 300mg/mL, which equals an increase greater than 15,000-fold. The lipophilicity of the prodrugs has been determined by their HPLC capacity factors k'. The stability of selected compounds was determined. The hydrolysis rates follow pseudo-first order kinetics. In order to assess the immunological activity, the prodrugs were tested using tumor necrosis factor-alpha and interleukin-2 inhibition assays. Selected compounds were additionally investigated on their abililty to inhibit the local Shwartzman reaction, an assay to determine the vascular permeability. The prodrugs retained high effectiveness in the inhibition of TNF-alpha release. Our results indicated that the more stable prodrugs exhibited higher activity in the immunological assays. Some compounds showed higher activity than thalidomide itself, suggesting a high affine binding to the pharmacophore. In conclusion, the prodrugs exhibited high water solubility and high activity and might therefore be used in therapeutic applications.


Assuntos
Interleucina-2/antagonistas & inibidores , Interleucina-2/biossíntese , Fenômeno de Shwartzman/metabolismo , Talidomida/síntese química , Talidomida/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Sítios de Ligação , Estabilidade de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Masculino , Camundongos , Permeabilidade , Solubilidade , Talidomida/química , Água/química
3.
Scand J Immunol ; 48(4): 397-402, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9790310

RESUMO

Thalidomide is reported to have immunomodulatory and anti-inflammatory effects, which have led to its use in the treatment of a number of immune-mediated disorders, including leprosy, discoid lupus and Behcet's disease, and to prevent immunological rejection phenomena following skin and bone marrow grafts. Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated demyelinating autoimmune disease, which represents an animal model for the study of the immunopathogenesis and immunotherapy of Guillain-Barré syndrome (GBS) in humans. We examined the effect of thalidomide in Lewis rats with EAN, which was induced by immunization with bovine peripheral nerve myelin (BPM) and complete Freund's adjuvant (CFA). Thalidomide prolonged clinical EAN when given at a dose of 200 mg/kg/day by gavage. This clinical effect was associated with increased numbers of inflammatory cells in sciatic nerve sections and elevated numbers of interferon-gamma (IFN-gamma) mRNA-expressing cells among lymph node mononuclear cells from thalidomide-treated EAN rats on day 17 postimmunization, i.e. at the peak of clinical EAN. The finding that thalidomide prolongs clinical EAN is in agreement with the clinical polyneuropathy reported in patients receiving treatment with thalidomide and limits its clinical usefulness.


Assuntos
Imunossupressores/imunologia , Imunossupressores/farmacologia , Neurite Autoimune Experimental/imunologia , Talidomida/imunologia , Talidomida/farmacologia , Animais , Bovinos , Interferon gama/imunologia , Bainha de Mielina/imunologia , Neurite Autoimune Experimental/induzido quimicamente , Ratos , Ratos Endogâmicos Lew
4.
Ann Intern Med ; 128(6): 443-50, 1998 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-9499327

RESUMO

BACKGROUND: Recurrent oral and genital ulcers are the most frequent problem in the management of the Behçet syndrome. Uncontrolled experience suggests that thalidomide may help prevent recurrences of these ulcers. OBJECTIVE: To determine the efficacy of two thalidomide dosages in the treatment of mucocutaneous lesions of the Behçet syndrome. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Specialist outpatient clinic for the Behçet syndrome in Turkey. PATIENTS: 96 male patients with the Behçet syndrome who primarily had mucocutaneous lesions without major organ involvement. INTERVENTION: Thalidomide, 100 mg/d or 300 mg/d, or placebo for 24 weeks. MEASUREMENTS: Sustained absence of any oral and genital ulceration during treatment (complete response) and changes in the number of mucocutaneous lesions. An additional evaluation was done 4 weeks after treatment ended. RESULTS: A complete response occurred in 2 of the 32 patients (6% [95% CI, 0.8% to 20.8%]) receiving thalidomide, 100 mg/d; in 5 of the 31 patients (16% [CI, 5.5% to 33.7%]) receiving thalidomide, 300 mg/d; and in none of the 32 patients (0% [CI, 0% to 10.9%]) receiving placebo (P = 0.031). The suppressive effect of thalidomide with either dosage was evident at 4 weeks for oral ulcers (P < 0.001) and at 8 weeks for genital ulcers (P < 0.001) and follicular lesions (P = 0.008). This effect persisted during treatment but diminished rapidly after treatment was discontinued. Both thalidomide dosages led to significant increases in the number of erythema nodosum lesions during the first 8 weeks of treatment (P = 0.03). Polyneuropathy developed in 4 patients (1 in the 100-mg/d group and 3 in the 300-mg/d group); in 3 of these patients, the condition was diagnosed after the trial had ended. CONCLUSIONS: Thalidomide is effective for treating the oral and genital ulcers and follicular lesions of the Behçet syndrome. A dosage of 100 mg/d is as effective as a dosage of 300 mg/day.


Assuntos
Síndrome de Behçet/tratamento farmacológico , Doenças dos Genitais Masculinos/tratamento farmacológico , Úlceras Orais/tratamento farmacológico , Talidomida/administração & dosagem , Úlcera/tratamento farmacológico , Adolescente , Adulto , Método Duplo-Cego , Esquema de Medicação , Seguimentos , Humanos , Masculino , Doenças do Sistema Nervoso/induzido quimicamente , Placebos , Recidiva , Fases do Sono/efeitos dos fármacos , Estatísticas não Paramétricas , Talidomida/efeitos adversos , Resultado do Tratamento
5.
Arch Pharm (Weinheim) ; 331(1): 7-12, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9507696

RESUMO

The synthesis of 5'-substituted thalidomide analogs is described. The amino acids 2 necessary to synthesize the target compounds were prepared by Michael reaction. Condensation of 2 with phthalic anhydrides followed by reaction with urea yielded 4 as diastereomeric mixtures. Furthermore glutethimide (5) was brominated by an improved method and the resulting compound 6 was reacted in several steps with sodium azide, hydrogen, and phthalic anhydride to give 8. In a similar manner, 6 was reacted with sodium azide and various phthalic anhydrides to give 9, 10, and 11. All final compounds were tested in vitro for their inhibitory activity on the release of TNF-alpha, using stimulated peripheral mononuclear blood cells (PBMCs). Compounds with an additional aromatic substituent in position 5' of the thalidomide molecule were more active than thalidomide. Compound 11 was able to reduce increased levels of IL-2 in vitro.


Assuntos
Talidomida/análogos & derivados , Talidomida/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Humanos , Técnicas In Vitro , Relação Estrutura-Atividade , Talidomida/química
6.
Inflamm Res ; 46(10): 392-7, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9372310

RESUMO

OBJECTIVE AND DESIGN: Thalidomide is very effective in the treatment of idiopathic aphthous stomatitis, characterized by recurrent focal intramucosal leukocytic vasculitis. The mode of action of thalidomide in this clinical entity may include inhibition of the extravasation of leukocytes. Therefore, we studied the effect of thalidomide on different steps of leukocyte migration by intravital microscopy. MATERIAL: Male Syrian golden hamsters were used. TREATMENT: Leukocyte migration in buccal mucosa of the hamster cheek pouch was elicited by the local application of lipopolysaccharide (LPS, 20 micrograms/ml) or murine tumor necrosis factor-alpha (muTNF-alpha, 10 ng/ml). (+)-Thalidomide (20-200 mg/kg i.p.) was administered 60 min before the local application of LPS or muTNF-alpha. Dexamethasone (2 x 1.0-10 mg/kg i.p.) was administered 18 h and 60 min before topical LPS application. METHODS: The numbers of rolling, firmly adherent and migrating leukocytes were estimated by intravital microscopy up to 165 min after the topical applications of LPS or muTNF-alpha and evaluated by an interactive image analysis software. RESULTS: Thalidomide (20-200 mg/kg i.p.) dose-dependently inhibited LPS-stimulated perivenular leukocyte migration by up to 87 +/- 5% and muTNF-alpha-induced leukocyte migration by up to 78 +/- 4%. Dexamethasone (2 x 1.0-10 mg/kg i.p.) inhibited LPS-stimulated leukocyte migration by up to 85 +/- 13%. (+)-Thalidomide (200 mg/kg i.p.) inhibited LPS-stimulated rolling by 80 +/- 5% and reduced the number of firmly adherent leukocytes by about 40%. Dexamethasone (2 x 10 mg/kg i.p.) did not reduce the number of rolling leukocytes but inhibited leukocyte adherence by 72 +/- 9%. CONCLUSIONS: These results show that (+)-thalidomide predominantly inhibits leukocyte rolling and thus differs from the glucocorticoid dexamethasone. The inhibition of LPS- or muTNF-alpha-induced leukocyte extravasation by thalidomide may account for some of its clinical activities.


Assuntos
Imunossupressores/farmacologia , Inflamação/patologia , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Mucosa Bucal/patologia , Talidomida/farmacologia , Animais , Adesão Celular/efeitos dos fármacos , Bochecha , Quimiotaxia de Leucócito/efeitos dos fármacos , Cricetinae , Imunossupressores/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos , Masculino , Mesocricetus , Camundongos , Microscopia/métodos , Talidomida/uso terapêutico , Fator de Necrose Tumoral alfa
7.
Clin Exp Immunol ; 108(3): 428-31, 1997 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9182887

RESUMO

Thalidomide, a drug likely to affect the cytokine pattern, was administered orally to mice at various stages of CIA. Treatment (150 mg/kg per day by gavage, 5 days/week), started 6 weeks post-immunization, i.e. at the height of the disease, significantly reduced arthritis, and appeared also to reduce the level of inflammation as judged by neutrophil chemiluminescence. With treatment started 9 weeks post-immunization the effect on arthritis was no longer statistically significant, and when started at 14 weeks was lost. Over a dose range of up to 150 mg/kg per day the treatment had no effect on either interferon-gamma (IFN-gamma) or IL-4 mRNA levels. The treatment is therefore not likely to have operated via a shift in the Th1/Th2 balance.


Assuntos
Artrite/tratamento farmacológico , Colágeno/imunologia , Células Th1/fisiologia , Células Th2/fisiologia , Talidomida/uso terapêutico , Animais , Artrite/imunologia , Camundongos , Camundongos Endogâmicos DBA , Fator de Necrose Tumoral alfa/biossíntese
8.
Clin Neuropharmacol ; 20(2): 152-64, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9099468

RESUMO

The effects of thalidomide and, for reference, dexamethasone on T- and B-cell functions were assayed in vitro in Lewis rats with experimental allergic neuritis induced by active immunization with bovine peripheral nerve myelin (BPM) and complete Freund's adjuvant. Thalidomide and dexamethasone at the concentration ranges 10(-5)-10(-7) g/ml and 4 x 10(-5)-4 x 10(-9) g/ml, respectively, both inhibited phytohemagglutinin (PHA)- and BPM-induced T-cell proliferation as well as levels of PHA- and BPM-reactive interferon (IFN)-gamma-secreting cells, reflecting the suppression of Th1-like cells. The effect of dexamethasone was most pronounced on PHA-induced T-cell proliferation and IFN-gamma secretion, whereas the effect of thalidomide was most pronounced on BPM-induced T-cell proliferation and IFN-gamma secretion. Thalidomide reduced the B-cell responses to both BPM and Mycobacterium tuberculosis purified protein derivative, but to a lesser extent than dexamethasone. The in vitro design described could be useful to evaluate compounds with putative immunomodulatory activities. The inhibitory effects of thalidomide on autoantigen-induced Th1-cell functions may warrant the use of this substance in T-cell-mediated autoimmune diseases.


Assuntos
Linfócitos B/efeitos dos fármacos , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Neurite Autoimune Experimental/imunologia , Linfócitos T/efeitos dos fármacos , Talidomida/farmacologia , Animais , Autoantígenos , Linfócitos B/imunologia , Dexametasona/farmacologia , Imunoglobulina G/imunologia , Interferon gama/imunologia , Linfonodos/imunologia , Masculino , Proteína P2 de Mielina , Neurite Autoimune Experimental/etiologia , Ratos , Ratos Endogâmicos Lew , Linfócitos T/imunologia
10.
Biol Blood Marrow Transplant ; 2(2): 86-92, 1996 May.
Artigo em Inglês | MEDLINE | ID: mdl-9118303

RESUMO

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.


Assuntos
Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/efeitos adversos , Talidomida/efeitos adversos , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Talidomida/uso terapêutico , Transplante Homólogo
11.
Immunopharmacology ; 31(2-3): 213-21, 1996 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8861747

RESUMO

The mode of action of thalidomide (THD) in clinical cases of vasculitis is still not clear. Expression of adhesion molecules on endothelial cell lines was therefore assessed in vitro. THD is capable of changing the density of tumor necrosis factor alpha (TNFalpha) induced ICAM-1 (CD54), VCAM-1 (CD106) and E-selectin antigens on HUVEC. Furthermore, modulation of L-selectin (CD62L) by THD can be demonstrated on human leukocytes in vitro. The molecules investigated are involved in the neutrophil-endothelial cell interaction and participate in the adhesion cascade. Blunting of cytokine induced up-regulation of these adhesion molecules may account at least in part for anti-vasculitic effects of thalidomide.


Assuntos
Moléculas de Adesão Celular/efeitos dos fármacos , Glicoproteínas de Membrana/efeitos dos fármacos , Talidomida/farmacologia , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/biossíntese , Regulação para Baixo/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Leucócitos/metabolismo , Glicoproteínas de Membrana/biossíntese
12.
Chirality ; 8(5): 390-6, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8900028

RESUMO

The question whether the immunomodulating activity of rac-thalidomide resides in either the (-)-(S)- or the (+)-(R)-enantiomer was addressed by synthesis and separation of pure enantiomers of thalidomide analogues which carry a methyl-group at the asymmetric carbon atom and are thus prevented from racemization. The effect of the pure enantiomers of the thalidomide-analogues and also of the enantiomers of thalidomide on release of TNF-alpha was tested in vitro by using stimulated peripheral mononuclear blood cells. Both enantiomers of thalidomide inhibited the release of TNF-alpha equally well at low concentrations (5 and 12.5 micrograms/ml) but at higher concentrations (25 and 50 micrograms 50 micrograms/ml) there was a weak but statistically significant selectivity towards the (-)-(S)-enantiomer. In the case of the configuration-stable thalidomide-analogues there was a very pronounced and statistically significant enantioselectivity towards the (S)-form even at lower concentrations (> or = 5 micrograms/ml). The (S)-enantiomers of the thalidomide-analogues differed in their inhibitory potency from (-)-(S)-thalidomide suggesting that the introduction of the methyl-group increases the TNF-alpha-inhibitory activity while the reduction of one of the carbonyl-functions in the glutarimide-moiety to a methylene-group decreases activity. The effect of these small molecular alterations on activity and the enantioselectivity towards the (S)-enantiomers may indicate that thalidomide and its analogues directly interact with one or several cellular target-proteins.


Assuntos
Imunossupressores/farmacologia , Talidomida/análogos & derivados , Talidomida/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Células Cultivadas , Humanos , Imunossupressores/química , Cinética , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Talidomida/química
13.
FEMS Immunol Med Microbiol ; 12(3-4): 165-74, 1995 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8745000

RESUMO

The Shwartzman reaction is an animal model displaying histopathological vasculitis phenomena. Extravasation and swelling due to increased vascular permeability and cellular infiltration, which are hallmarks of the Shwartzman reaction, were evaluated as leakage of i.v.-injected Evans Blue dye and by histological and immunohistological characteristics in rabbits and mice. (+/-)-Thalidomide, (-)-thalidomide, (+)-thalidomide and dexamethasone inhibited the increase of vascular permeability in the local Shwartzman reaction. Histologically, the intensity of the Shwartzman reaction was reduced. In mice thrombus formation and leukocytoclastic vasculitis was inhibited by (+/-)-thalidomide and (+)-thalidomide. ICAM-1 expression was markedly reduced after (+)-thalidomide injection. Thalidomide and dexamethasone pretreatment reduced Mac-1 expression on perivascular infiltrated granulocytes. The inhibitory effect of thalidomide on vasculitis of the Shwartzman reaction may thus be related to reduction of adhesion molecule expression.


Assuntos
Fenômeno de Shwartzman/metabolismo , Fenômeno de Shwartzman/patologia , Talidomida/farmacologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Dexametasona/farmacologia , Molécula 1 de Adesão Intercelular/biossíntese , Antígeno de Macrófago 1/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Coelhos
14.
Blood ; 86(9): 3604-9, 1995 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-7579470

RESUMO

Thalidomide has been reported to be an effective agent for treatment of chronic graft-versus-host disease (CGVHD). To determine the efficacy of this agent in patients with refractory CGVHD a total of 80 patients who failed to respond to prednisone (PSE) or PSE and cyclosporine (CSA) were treated with thalidomide. Sixteen patients (20%) had a sustained response, 9 with a complete remission and 7 with a partial response. Twenty-nine patients (36%) had thalidomide discontinued because of side effects, which included sedation, constipation, neuritis, skin rash, and neutropenia. Side effects were reversible with drug discontinuation except for mild residual neuritis in one case. Rashes and neutropenia have not previously been reported as thalidomide side effects when used for CGVHD treatment. We conclude thalidomide is immunosuppressive and active in the treatment of CGVHD. A high incidence of reversible side effects limited dose intensity and reduced the number of patients who could benefit from treatment.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Toxidermias/etiologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Imunossupressores/uso terapêutico , Neutropenia/induzido quimicamente , Terapia de Salvação , Talidomida/uso terapêutico , Adolescente , Adulto , Transplante de Medula Óssea/mortalidade , Criança , Doença Crônica , Constipação Intestinal/induzido quimicamente , Ciclosporina/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doenças Hematológicas/terapia , Humanos , Infecções/mortalidade , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Neurite (Inflamação)/induzido quimicamente , Prednisona/uso terapêutico , Indução de Remissão , Taxa de Sobrevida , Talidomida/efeitos adversos , Resultado do Tratamento
15.
Exp Toxicol Pathol ; 47(2-3): 167-72, 1995 May.
Artigo em Inglês | MEDLINE | ID: mdl-7580103

RESUMO

A local Shwartzman response was elicited in rabbits by an intradermal injection of the Salmonella typhosa endotoxin lipopolysaccharide (LPS) followed 24 hours later by an intravenous challenge injection with zymosan. After the intravenous challenge, necrotizing vasculitis developed in the prepared skin sites which was characterized by microthrombi, accumulation of neutrophil granulocytes, fibrin deposition and extravasation of red blood cells. Evans' blue extravasation into the altered tissue was significantly reduced, and histologically, the intensity of the Shwartzman reaction in the skin was reduced by pretreatment with thalidomide and dexamethasone. The mechanism of reduction of an LPS-induced local Shwartzman reaction by thalidomide is discussed.


Assuntos
Lipopolissacarídeos , Fenômeno de Shwartzman/patologia , Pele/patologia , Animais , Dexametasona/uso terapêutico , Masculino , Coelhos , Fenômeno de Shwartzman/induzido quimicamente , Fenômeno de Shwartzman/tratamento farmacológico , Pele/irrigação sanguínea , Talidomida/uso terapêutico , Zimosan/toxicidade
16.
Acta Neuropathol ; 89(5): 415-9, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-7618439

RESUMO

In addition to the well-known teratogenic effect of thalidomide, previous studies have revealed mild immunosuppressive properties and, more recently, an anti-angiogenic activity. To find out more about the specificity of these effects we studied the influence of orally administered thalidomide on Wallerian degeneration in rats. Wallerian degeneration is a potent experimental model for studying reproducible cell proliferation in vivo. Examination of distal nerve segments of transected sciatic nerves from rats that had been treated with thalidomide (2 x 250 mg/kg per day) revealed a significant reduction of endoneurial cell counts at 10-15 days after surgery compared to that seen in controls. This effect was not statistically significant, at a very early stage of Wallerian degeneration, i.e., at 5 days after transection of the nerve. Subperineurial edema and phagocytosis was also reduced, although this was not statistically significant. This apparently nonspecific inhibitory effect of thalidomide during early Wallerian degeneration shown in the present study should be investigated further for its possible relationship to other previously established inhibitory activities of thalidomide, especially its immunosuppressive effect in man.


Assuntos
Edema Encefálico/patologia , Bainha de Mielina/fisiologia , Fagocitose/efeitos dos fármacos , Talidomida/farmacologia , Degeneração Walleriana/efeitos dos fármacos , Animais , Divisão Celular/efeitos dos fármacos , Ratos , Ratos Wistar , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia
17.
J Inflamm ; 46(4): 177-211, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8878794

RESUMO

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.


Assuntos
Adjuvantes Imunológicos/farmacologia , Talidomida/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Fenômenos Químicos , Físico-Química , Citocinas/metabolismo , Humanos , Hipnóticos e Sedativos/farmacologia , Leucócitos/efeitos dos fármacos , Infecções por Mycobacterium , Talidomida/química , Talidomida/farmacocinética , Vasculite/microbiologia , Vasculite/patologia
18.
Clin Infect Dis ; 17(4): 637-43, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8268344

RESUMO

The existence of chronic trichinosis as a disease entity is still a matter of debate. For 10 years after an outbreak of infection with Trichinella spiralis, we conducted a prospective controlled study of the patients involved. At the termination of this investigation, we undertook clinical, biochemical, serological, immunologic, neuroradiological, radiological, and psychological studies of 128 originally infected persons and 16 controls. The categories of symptoms most often documented in persons who had been infected were muscular (90%), ocular (59%), neurological (52%), and psychological (52%). Impaired muscle strength (56%), conjunctivitis (55%), and impaired coordination (32%) were the clinical manifestations most frequently encountered. Thirty-eight percent of the 128 originally infected patients still had IgG antibodies to T. spiralis after 10 years. Magnetic resonance imaging of the brain revealed no abnormalities. No calcifications of residual larvae were detected by mammography or muscle biopsy. The level of performance in psychometric tests was lower in the originally infected population than in the general population. Although patients who had had trichinosis differed significantly from controls in terms of a variety of parameters even after 10 years, we found insufficient evidence on which to conclude that chronic trichinosis exists as a distinct entity.


Assuntos
Trichinella spiralis , Triquinelose , Adulto , Idoso , Animais , Anticorpos Anti-Helmínticos/sangue , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Doença Crônica , Estudos de Coortes , Conjuntivite/etiologia , Surtos de Doenças , Edema/etiologia , Feminino , Alemanha/epidemiologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Estudos Prospectivos , Radiografia , Trichinella spiralis/imunologia , Triquinelose/complicações , Triquinelose/diagnóstico por imagem , Triquinelose/epidemiologia , Triquinelose/patologia , Triquinelose/psicologia
19.
Br J Dermatol ; 128(4): 388-92, 1993 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8494751

RESUMO

It has been suggested that T lymphocytes expressing gamma delta T-cell receptors could play an important role in defence against some intracellular infectious pathogens. The present study was undertaken to characterize the occurrence and variable delta gene expression of T lymphocytes expressing the gamma delta T-cell receptor in oriental cutaneous leishmaniasis. Eleven cases of oriental cutaneous leishmaniasis were investigated by immunohistological analysis using an alkaline phosphatase-anti-alkaline phosphatase (APAAP) technique. In three cases, we observed an increased percentage of gamma delta T cells (about 20% of CD3+ cells). In these cases gamma delta T cells generally expressed the V delta 2 segment, and only rarely the V delta 1 gene product. V delta 2+ cells were predominantly localized in the dermis, and were virtually absent in the epidermal compartment. The rare gamma delta T cells observed in the epidermis were almost exclusively V delta 1+. This study demonstrates that an increase of gamma delta T cells may be found in oriental cutaneous leishmaniasis, although it is not a constant feature of the disease. The finding of a preferential expansion of the V delta 2 subset suggests that this subpopulation of gamma delta T cells might be selectively involved in the recognition of Leishmania antigens. The distinct compartmentalization of gamma delta T-cell subpopulations indicates that these subsets may recognize distinct sets of antigens.


Assuntos
Leishmaniose Cutânea/genética , Receptores de Antígenos de Linfócitos T gama-delta/análise , Antígenos de Protozoários/análise , Complexo CD3/análise , Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Contagem de Leucócitos , Linfócitos T/imunologia
20.
J Interferon Res ; 13(1): 39-41, 1993 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8454909

RESUMO

The clinical, parasitological, hematological, and serological evolution of visceral leishmaniasis in Brazilian patients was assessed during treatment with human recombinant interferon-gamma (rIFN-gamma; 0.1 mg/m2 i.m. days 1-14) followed by pentavalent antimony (Sbv; 10 mg/kg days 22-28). At day 30, 6 patients had improved, 2 had slightly improved, and 1 patient had deteriorated. IFN-gamma was well tolerated in the dose tested and may be very effective as an adjunct to conventional therapy with antimony.


Assuntos
Antimônio/uso terapêutico , Interferon gama/uso terapêutico , Leishmaniose Visceral/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Masculino , Projetos Piloto , Proteínas Recombinantes
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