METABOLIC PATHWAY AND ITS RELATIONSHIP TO THE BIOLOGICAL ACTIVITY OF SOME TUBERCULOSTATIC AND LEPROSTATIC AGENTS.
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Antitubercular Agents↗
SEARCH · PubMed Health
Results for “Leprostatic Agents”
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
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Thalidomide back--under strict control.
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Drug Industry↗
[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↗
Thalidomide: current and potential clinical applications.
More than three decades after its withdrawal from the world marketplace, thalidomide is attracting growing interest because of its reported immunomodulatory and anti-inflammatory properties. Current evidence indicates that thalidomide reduces the activity of the inflammatory cytokine tumor necrosis factor (TNF)-alpha by accelerating the degradation of its messenger RNA. Thalidomide also inhibits angiogenesis. Recently, the drug was approved for sale in the United States for the treatment of erythema nodosum leprosum, an inflammatory complication of Hansen's disease. However, it has long been used successfully in several other dermatologic disorders, including aphthous stomatitis, Behçet's syndrome, chronic cutaneous systemic lupus erythematosus, and graft-versus-host disease, the apparent shared characteristic of which is immune dysregulation. Many recent studies have evaluated thalidomide in patients with human immunodeficiency virus (HIV) infection; the drug is efficacious against oral aphthous ulcers, HIV-associated wasting syndrome, HIV-related diarrhea, and Kaposi's sarcoma. To prevent teratogenicity, a comprehensive program has been established to control access to the drug, including registration of prescribing physicians, dispensing pharmacies, and patients; mandatory informed consent and education procedures; and limitation of the quantity of drug dispensed. Clinical and, in some patients, electrophysiologic monitoring for peripheral neuropathy is indicated with thalidomide therapy. Other adverse effects include sedation and constipation. With appropriate safeguards, thalidomide may benefit patients with a broad variety of disorders for which existing treatments are inadequate.
Angiogenesis Inhibitors↗
Thalidomide: a review of approved and investigational uses.
BACKGROUND: Thalidomide is best known as a major teratogen that caused birth defects in up to 12,000 children in the 1960s. More recently, this agent has been approved by the US Food and Drug Administration for the treatment of erythema nodosum leprosum (ENL) through a restricted-use program. Its immunomodulatory, anti-inflammatory, and antiangiogenic properties are currently under study in a number of clinical conditions. OBJECTIVE: This article reviews the pharmacology of thalidomide; its approved and off-label uses in dermatologic, oncologic, and gastrointestinal conditions; and adverse events associated with its use. METHODS: Relevant articles were identified through searches of MEDLINE (1966-June 2002), International Pharmaceutical Abstracts (1970-June 2002), and EMBASE (1990-June 2002). Search terms included but were not limited to thalidomide, pharmacokinetics, pharmacology, therapeutic use, and teratogenicity, as well as terms for specific disease states and adverse events. Further publications were identified from the reference lists of the reviewed articles. Abstracts of recent symposia were obtained from the American Society of Clinical Oncology Web site. RESULTS: Thalidomide is thought to exert its therapeutic effect through the modulation of cytokines, particularly tumor necrosis factor-alpha. In addition to its approved indication for ENL, thalidomide has been studied in various other conditions, including graft-versus-host disease, discoid lupus erythematosus, sarcoidosis, relapsed/refractory multiple myeloma, Waldenstrom's macroglobulinemia, myelodysplastic syndromes, acute myeloid leukemia, myelofibrosis with myeloid metaplasia, renal cell carcinoma, malignant gliomas, prostate cancer, Kaposi's sarcoma, colorectal carcinoma, oral aphthous ulcers, Behçet's disease, Crohn's disease, and HIV/AIDS-associated wasting. Adverse events most frequently associated with its use include somnolence, constipation, rash, peripheral neuropathy, and thromboembolism. CONCLUSIONS: Use of thalidomide is limited by toxicity, limited efficacy data, and restricted access. Evidence of its efficacy in conditions other than ENL awaits the results of controlled clinical trials.
Abnormalities, Drug-Induced↗
Therapy for feline dermatoses.
This article compiles information on various therapies used in feline dermatology. Information on the following therapeutic agents and devices is discussed: antibiotics, antifungals, antileprosy drugs, antiparasiticides, antivirals, antihistamines, behavior modification drugs, fatty acids, progestogens, steroids, immunomodulating drugs, chemotherapeutic/immunosuppressive agents, retinoids, mechanical devices, hyposensitization, immunotherapy, food elimination trials, hypoallergenic diets, and miscellaneous topical agents such as polyhydroxydine solution, tar, and benzocaine-containing creams.
Animals↗
Thalidomide: the past, present, and future.
Treatment Review is intended to inform and update nurses about treatments relevant to HIV/AIDS. Product information presented in this column does not imply endorsement by the Association of Nurses in AIDS Care.
Erythema Nodosum↗
Thalidomide approval brings tight restrictions on access.
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Drug Approval↗
A case study in Hansen's disease acquired after heart transplant.
Hansen's disease, leprosy, is a chronic infectious disease caused by the acid-fast bacillus Mycobacterium leprae. There are multiple forms of the disease ranging from the relatively benign to the progressive, malignant lepromatous leprosy. There is effective antimicrobial treatment available that is capable of curing the disease. We report the case of a post heart transplant patient acquiring Hansen's disease.
Animals↗
Effects of antituberculosis and antileprosy drugs on mycobacteriophage D29 growth.
The minimal inhibitory concentrations of antituberculosis and antileprosy drugs were determined for Mycobacterium aurum. The concentrations that reduced the final yield of bacteriophage D29R1 by 50% and the time during the replication cycle at which the drugs completely inhibited phage production were estimated. THe 50% inhibitory concentration/minimal inhibitory concentration ratios were close to 1.0 for clofazimine, colistin, rifampin, and streptomycin; these ratios were high for dapsone (diaminodiphenylsulfone) and isoniazid. Ethambutol (minimal inhibitory concentration, 1.0 micrograms/ml) was without effect on viral growth.
Antitubercular Agents↗
Comparative in vitro activities of 20 fluoroquinolones against Mycobacterium leprae.
The in vitro activities of 20 fluoroquinolones against Mycobacterium leprae were evaluated by using the BACTEC 460 system. M. leprae was incubated in BACTEC 12B medium at 33 degrees C under reduced oxygen for 2 to 3 weeks in the presence of fluoroquinolones at 0.31 to 5 micrograms/ml. Activity was determined by a reduction in 14CO2 evolution compared with that of drug-free controls. Of the commercially available agents, ofloxacin was most active, while enoxacin and norfloxacin were inactive. However, a number of newer fluoroquinolones (AT-4140, OPC-17100, OPC-17066, PD-117596, PD-124816, PD-127391, and WIN-57273), all containing a cyclopropyl group at R-1 and, with the exception of WIN-57273, either a halogen or methyl group at R-8, were more active than ofloxacin in vitro. Further in vivo evaluations of these agents should help determine their potential for use against leprosy.
4-Quinolones↗
Dermatologic and nondermatologic uses of thalidomide.
OBJECTIVE: To review published data on thalidomide, with emphasis on current knowledge about mechanism of action, new and/or potential dermatologic and nondermatologic therapeutic applications, well-known and emerging adverse effects, and current indications for its safe use. DATA SOURCES: Review articles, in vitro research studies, references from retrieved articles, case reports, and clinical trials were identified from a computerized literature search using MEDLINE and OVID (1966-January 2003) and on the Cochrane Clinical Trials Register (January 2003). Information available from meetings' abstract books, Internet, or pharmaceutical companies was also considered. STUDY SELECTION AND DATA EXTRACTION: All articles identified as relevant, including those from non-English literature, were considered in an attempt to provide to the reader both the theoretical basis and practical guidelines for thalidomide pharmacotherapy. DATA SYNTHESIS: Thalidomide has hypnosedative, antiangiogenic, antiinflammatory, and immunomodulatory properties. Moreover, it has been shown to selectively inhibit the production of tumor necrosis factor-alpha and reduce the expression of various integrin receptors on the membrane of leukocytes and other cell types in a dose-dependent fashion. Controlled trials demonstrated the efficacy of thalidomide in a number of diseases, including erythema nodosum leprosum, lupus erythematosus, aphthosis, graft-versus-host disease, prurigo nodularis, and actinic prurigo. Single case reports or studies in small series have also suggested a possible role for thalidomide in numerous other dermatologic and nondermatologic disorders. Possibly severe and sometimes irreversible risks related to the clinical use of thalidomide include teratogenicity and neurotoxicity. CONCLUSIONS: Although teratogenicity and neurotoxicity are significant adverse effects requiring cautious use, thalidomide is an effective therapeutic modality in a variety of difficult-to-treat disorders and, providing careful selection of patients, should offer an acceptable risk-to-benefit ratio.
Angiogenesis Inhibitors↗
Deep vein thrombosis: a rare complication of thalidomide therapy in recurrent erythema nodosum leprosum.
A case of deep-vein thrombosis is reported in a female patient with multibacillary leprosy who received pulses of dexamethasone and cyclophosphamide for recurrent ENL that had not responded to prednisone and thalidomide.
Adult↗
Thalomid (Thalidomide) capsules: a review of the first 18 months of spontaneous postmarketing adverse event surveillance, including off-label prescribing.
The sedative/hypnotic thalidomide was withdrawn from the worldwide market nearly 40 years ago, because of its teratogenic and neurotoxic effects. Thalidomide was later found to very effectively suppress erythema nodosum leprosum (ENL). The US Food and Drug Administration (FDA) has approved Thalomid (thalidomide) capsules for the acute treatment of the cutaneous manifestations of moderate to severe ENL. Thalidomide is currently under investigation for the treatment of a wide variety of diseases, including conditions thought to have an inflammatory or immune basis, malignancies and complications of infection with HIV. Interest in the potential anti-inflammatory, immunomodulatory and anti- angiogenic effects of thalidomide has resulted in off-label use of prescription thalidomide. During the first 18 months of spontaneous postmarketing adverse event surveillance for Thalomid, 1210 spontaneous postmarketing adverse event reports were received for patients treated with prescription thalidomide for all therapeutic indications, including off-label use. The most common adverse events spontaneously reported would have been expected on the basis of the current Thalomid labelling/product information. The current labelling/product information reflects what was known about the risks associated with thalidomide therapy in limited patient populations at the time of the approval of Thalomid. With the postmarketing use of thalidomide in populations other than patients with ENL, it becomes increasingly important to identify patient groups that may be particularly susceptible to specific adverse drug effects and to identify conditions under which specific adverse events may be more likely to occur. Oncology patients may represent a patient population with increased susceptibility to thalidomide-associated adverse effects, including thromboembolic events. Consideration of the spontaneous postmarketing safety surveillance data may help to identify and characterise factors associated with increased risk in this and other patient groups. Serious unexpected adverse events reported with sufficient frequency to signal previously undetected product-event associations for which there may potentially be plausible evidence to suggest a causal relationship have included seizures and Stevens-Johnson syndrome. The potential effects of thalidomide on wound healing are also being closely monitored. Premarketing human clinical trials of drug products are inherently limited in their ability to detect adverse events. Broader postmarketing experience with thalidomide in more varied patient populations and more experience in the setting of long term thalidomide use will increase our ability to detect rare adverse events and to identify signals that may need to be evaluated in more controlled settings.
Angiogenesis Inhibitors↗
Thalidomide's tightly controlled "comeback".
Thalidomide has anti-inflammatory properties and shows promise for treating a variety of infectious and autoimmune diseases, but it must be used with strict precautions.
Autoimmune Diseases↗
[Thalidomide--a dreaded drug with new indications].
BACKGROUND: Thalidomide was introduced as a non-toxic sleeping pill in 1957 and was prescribed in more than 20 countries. In 1961 the link between congenital limb defects and thalidomide use in pregnancy was proven, resulting in withdrawal of the drug. MATERIAL AND METHODS: On the basis of literature searches and personal experience we review the effects and use of thalidomide today. RESULTS: In vitro, thalidomide has immunoregulatory properties. This has lead to the administration of thalidomide in many immunological diseases. In 1964 it was discovered that thalidomide was effective against erythema nodosum leprosum. Thalidomide also has effect on aphthous stomatitis and Behçet's disease. The effect is more uncertain in graft-versus-host-disease, rheumatoid arthritis and Crohn's disease. Thalidomide reduces angiogenesis in experimental animals, and this has led to several studies of thalidomide as a possible anticancer drug. Advanced or resistant multiple myeloma may be a new target for thalidomide; at least 30% of these patients obtain response during treatment. Results indicate that patients with breast cancer and glioma do not benefit from treatment with thalidomide. INTERPRETATION: Thalidomide has proven to be effective in the treatment of erythema nodosum leprosum and aphthous stomatitis. It is also effective in advanced multiple myeloma, but not in other cancers.
Abnormalities, Drug-Induced↗
Thalidomide: 40 years on.
Thalidomide was marketed in the late-1950s as a sedative and tranquilliser of exceptionally low general toxicity, but in 1961 it was implicated separately by Lenz and MacBride as the cause of the epidemic of congenital malformations that had been puzzling the world for some years. It is a very potent teratogen in humans, but in few other mammalian species; damage to the embryo is produced at specific stages of gestation, but the mechanism of embryopathic action is still not understood. Following the withdrawal of the drug worldwide, it was consigned to the history of medical tragedies. In 1965, however, Sheskin discovered that it was effective in treating erythema nodosum leprosum, a distressing complication of leprosy. As the drug is neither an antibiotic nor an analgesic, its action was assumed to be immunosuppressive. In Brazil the drug was used widely with few regulatory controls, since when more than 100 cases of congenital malformation have appeared. Sheskin's discovery led to the experimental use of thalidomide in many other indications thought to possess some immunological component. In some cases, e.g. Behçet's syndrome, graft-versus-host disease and aphthous ulceration in HIV-positive patients, the drug has been shown to possess some efficacy. And there is some evidence that it inhibits the replication of one of the immunodeficiency viruses. The AIDS community in the US has exerted much pressure on the FDA to allow the drug on to the market, although the use of a potent immunosuppressive drug of unknown mechanism in an immunodeficiency condition raises further questions. Thalidomide is not always beneficial; its use is associated with an increased mortality in epidermal necrolysis. In 1991, D'Amato confirmed it possessed antiangiogenic properties and this led to further trials in malignant conditions. Results were mixed, but those in multiple myeloma gave some grounds for optimism. In 1998, the FDA announced its extraordinary decision to grant marketing approval for thalidomide.
Anti-HIV Agents↗
[Thalidomide: new uses for an old drug].
Thalidomide was withdrawn from the market in the early sixties because of its teratogenic effects. Despite forty years of research, the mechanism of thalidomide embryopathy has remained unsolved. Thalidomide has various immunomodulatory effects. Thalidomide inhibits TNF alpha production, has T-cell costimulatory properties and modulates the expression of cell surface molecules on leukocytes in vivo. Thalidomide also has anti-angiogenic activity in vivo. Angiogenesis plays an important role in the pathogenesis of both solid tumours and hematologic malignancies such as multiple myeloma and lymphoma. In clinical studies, thalidomide has been used as an inhibitor of angiogenesis. Erythema nodosum leprosum is the only registered indication for the use of thalidomide in the United States of America. Thalidomide is also effective in the treatment of chronic graft-versus-host disease, mucocutaneous lesions in Behçet's syndrome and HIV infections, and multiple myeloma.
Angiogenesis Inhibitors↗