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The
Thalidomide's Come Back. La Talidomida, el regreso. *********************************** Este producto, caído en desgracia desde esa epoca, con el tiempo se le fue demostrando su utilidad en variadas patologías dermatológicas y no dermatológicas, y hoy
día, el 16 de Julio de 1.998 fue aprobado por la FDA Americana, para el tratamiento de la reacción leprosa. En ESTAS REFERENCIAS bibliográficas, queda plasmado un poco la historia de este producto de la casa CELGENE. AB - BACKGROUND AND DESIGN: An effective therapy is still unavailable for Jessner-Kanof lymphocytic infiltration of the skin. Thalidomide's efficacy was suggested in an open study. Twenty-eight patients were randomly assigned to receive thalidomide (100 mg/d) or placebo over a period of 2 months and were then switched to the other treatment. RESULTS: After the first period, 11 of 13 patients treated with thalidomide were in complete remission (CR), and there were two failures. There was no CR in the patients who received placebo (chi y2 = 17.5; P .0001). After the second period, nine of 14 patients who had received thalidomide were in CR. Eleven of the 13 patients who had received thalidomide during the first period were given placebo (two were unavailable for follow-up). Ten of them were in CR: four were still free of lesions at the end of the second period, and six experienced a relapse of their lesions after a mean duration of 26 +/- 10 (SD) days. A total of 25 patients participated in the two study periods; CR was observed in 19 (76%) after thalidomide therapy and in four (16%) after treatment with placebo (chi y2 = 11.1; P .001). Of 27 patients who received thalidomide, 16 (59%) were in CR after 1 month and 20 (74%) were in CR after 2 months. Two patients treated with thalidomide experienced neurologic changes that were not consistent with typical thalidomide-induced neuropathy. CONCLUSIONS: A therapeutic regimen of
thalidomide administered at a dosage of 100 mg/d for 2 months is able to
suppress the clinical symptoms of Jessner-Kanof lymphocytic infiltration of
the skin. The long-term risk-benefit has still to be evaluated.
AB - Many therapeutic agents have been proposed for treatment of steroid-resistant sarcoidosis. Because administration of low doses of thalidomide has been successful in treating other inflammatory diseases, it was used in a patient with systemic sarcoidosis who was unresponsive to corticosteroids and in a patient with pulmonary sarcoidosis, in whom Kaposi's sarcoma developed after a course of corticosteroid therapy. Thalidomide, 200 mg/day for 2 weeks followed by 100 mg/day for 11 weeks, was given. This treatment was effective in both patients. No adverse
reactions were observed. Thalidomide, 100 mg on alternate days, is still
being administered. No relapse has occurred. Thalidomide, particularly
because of its inhibition of the macrophage function, may be a useful
alternative therapy in steroid-resistant cases. In addition, the
correlation between the angiotensin-converting enzyme level and the
clinical improvement observed in our patients suggests a direct parallel
between angiotensin-converting enzyme and the activity of the granulomatous
process.
AB - In recent years, thalidomide has been used for the treatment of a variety of ulcerative and immunologic conditions. Several previous reports have suggested that thalidomide therapy is beneficial for patients with aphthous ulceration related to human immunodeficiency virus (HIV) infection. We describe the use of thalidomide in 20 HIV-infected patients with oropharyngeal, esophageal, and rectal ulceration. Nineteen patients
had a dramatic response to thalidomide therapy, with both subjective and
objective abatement in the signs and symptoms of their ulcerative disease.
The standard treatment course was 200 mg of thalidomide for 14 days (the
drug was administered at night). Four patients required additional courses
of treatment because symptoms recurred after thalidomide therapy was
stopped. Side effects due to thalidomide included rash (5 patients),
peripheral neuropathy (1 patient), and excessive fatigue (1 patient). There
did not appear to be any adverse immunologic effects in thalidomide-treated
patients. The mechanism of the effect of thalidomide is uncertain, although
recent studies have suggested that thalidomide selectively inhibits the
production of tumor necrosis factor alpha.
AB - BACKGROUND. Allogeneic bone marrow transplantation is an accepted therapy for hematologic cancer, aplastic anemia, and inherited immunodeficiencies. Chronic graft-versus-host disease (GVHD) is the principal complication in patients surviving more than 100 days. Thalidomide has been shown experimentally to be effective in treating GVHD. METHODS. We treated 23 patients with chronic GVHD refractory to conventional treatment and 21 patients with "high-risk" chronic GVHD (identified as having at least two of the following three risk factors: chronic GVHD that has evolved from acute GVHD, lichenoid skin or mucous-membrane changes, and hepatic dysfunction. Such patients have a high mortality rate.) with thalidomide in a dose that produced a plasma level of 5 micrograms per milliliter two hours after administration. Therapy was continued for three months after a complete response or for six months after a partial response. RESULTS. The overall actuarial survival of all
enrolled patients was 64 percent. Survival was 76 percent among the
patients receiving salvage therapy for refractory GVHD and 48 percent among
those with high-risk GVHD. A complete response was observed in 14 patients,
a partial response in 12 patients, and no response in 18. Side effects were
minor, most notably sedation in almost all patients. CONCLUSIONS. In this
preliminary trial, thalidomide appeared to be safe and effective for the
treatment of chronic GVHD. A trial comparing thalidomide with prednisone in
patients with newly diagnosed chronic GVHD will be required to demonstrate
its relative efficacy. AB - Thalidomide is well documented as being an effective drug in the
treatment of erythema nodosum leprosum (ENL). The mechanism of action of
thalidomide in ENL as well as the pathogenesis of ENL are yet to be fully
determined. Lepromatous leprosy patients experiencing ENL have been
reported to have an increase in the ratio of CD4+ to CD8+ cells in their
blood and ENL skin lesions. Thalidomide has been shown to cause a decrease
in the ratio of CD4+ to CD8+ lymphocytes in the blood of healthy males.
This decrease was due to a significant reduction in the numbers of Cd4+
lymphocytes and an apparent increase in the numbers of CD8+ lymphocytes. In
this study, thalidomide's effectiveness in halting chronic ENL and
arresting a relapse into ENL was consistently associated with a decrease in
the numbers of CD4+ lymphocytes in the blood of 2 male lepromatous leprosy
patients.
AB - A female patient with disfiguring lupus erythematosus profundus (LEP)
from the age of 13 years was found to have an isolated partial C4
deficiency, with reduced levels of both allotypes, C4A and C4B. A genetic
basis for the hypocomplementaemia was confirmed by a family study of
complement and HLA types which revealed heterozygous null alleles for C4A
and C4B in the proband. Marked improvement in her cutaneous lesions
occurred with thalidomide.
AB - A clinical experience of using thalidomide in type-2 lepra reaction
(ENL) in 90 male patients--57 with lepromatous leprosy (LL) and 33 with
borderline lepromatous leprosy (BL)--is described. All the patients
responded well although some took a longer time to improve. No major side
effects were observed except for giddiness in 10 and gastrointestinal
upsets in 7 patients. Thalidomide thus appears to be a very effective drug
in the treatment of severe type-2 lepra reaction and apart from its
historically well-documented embryopathic effects, does not seem to have
any other serious side effects in the patients under study.
AB - Combination CsA with corticosteroids is the most commonly used maintenance immunosuppressive regimen after cardiac transplantation, although their high-toxicity profiles frequently limit their clinical benefit. Immunosuppressive agents that would act synergistically with CsA but without the toxicity profile of corticosteroids would be clinically useful. Thalidomide was removed from the market due to its teratogenic effects, although it has known immunomodulatory activity. The purpose of this study was (1) to determine whether maintenance immunosuppression with thalidomide and subtherapeutic doses of CsA can help prevent rat cardiac allograft rejection; and (2) to compare its synergism with CsA to the commonly used corticosteroid, methylprednisolone. ACI-LEW allografts were all treated with subtherapeutic doses of CsA (10 mg/g/day, s.c.) for 4 days. When CsA was then discontinued, severe rejection developed by posttransplant day 14. Group 1 received CsA alone. Group 2 received in addition oral thalidomide 100 mg/day for 14 days. Groups 3, 4, and 5 received CsA and methylprednisolone (low dose: 0.2 mg/kg/day s.c.; moderate dose: 2.0 mg/kg/day s.c.; and high dose: 20 mg/kg/day s.c. Twelve histologic parameters of rejection were semiquantitatively graded 0-4, and total pathology scores were determined. The combination of thalidomide and
subtherapeutic CsA significantly reduced the severity of myocardial
necrosis, interstitial inflammation, interstitial edema, and the total
pathology score. Thalidomide was found to be equally as effective as low-,
moderate-, and high-dose methylprednisolone. The results of this study
suggest the potential clinical role of CsA and thalidomide in maintenance
immunosuppressive regimens, thereby avoiding the use of corticosteroids. AB - In an open study, 17 patients (16 women, 1 man) with refractory or severe rheumatoid arthritis were treated with thalidomide. Two withdrew from the study in the first weeks. Thirteen patients received 531 +/- 63 mg/day of thalidomide for 18.8 +/- 8.8 weeks; in 2 the dose was 300 mg/day during 62 and 65 weeks. Seven patients attained complete remission, 5 partial remission, and the last 3 no improvement at all. Remissions lasted 6 years in 1 patient, 2 years in 3, 1 year in one, and varied between 8 months and 8 weeks in 7. After relapse, 5 patients received a 2nd course of treatment and attained remission again. This lasted 24, 10, and 9 months in
3; two are taking 100 mg/day of thalidomide as a maintenance dose and
remain asymptomatic after 36 and 30 months. The side effects were
drowsiness, constipation, hard swelling of the lower limbs, erythema of the
face and limbs with local pruritus or burning sensation, hair loss, cough,
nasal obstruction, fever, and skin and mucosal dryness. In 8 patients there
was mild eosinophilia (less than 10%) and in 2 leukopenia. A 33-year-old
woman showed amenorrhea up to 2 months after stopping treatment. After a
2nd course of treatment, 2 patients developed peripheral sensory
neuropathy, which resolved spontaneously in 6 months. We believe these
findings justify controlled trials with this agent. Subfile: INDEX MEDICUS BACKGROUND & AIMS: Microsporidiosis is a common cause of chronic diarrhea in human immunodeficiency virus (HIV)-seropositive individuals and often does not respond to treatment. Fecal tumor necrosis factor alpha (TNF-alpha) is elevated in microsporidiosis; therefore, thalidomide, an anti-TNF-alpha agent, was used as therapy. METHODS: Eighteen subjects with chronic diarrhea caused by Enterocytozoon bieneusi that had not responded symptomatically to albendazole and 1 untreated subject with Encephalitozoon intestinalis received 1 month of thalidomide, 100 mg nocte. Clinical response was assessed by stool frequency and body weight, histological response by light microscopy with villus height/crypt depth ratios and electron microscopy, and immunologic response by fecal TNF-alpha level. RESULTS: Seven subjects with chronic diarrhea due to E. bieneusi had a complete clinical response, and 3 had a partial response to thalidomide. There was a significant decrease in stool frequency from 5.3 to 3.1 per day (P = 0.001), and weight increased significantly by 1.2 kg (P < 0.02). Thalidomide significantly increased the villus height/crypt depth ratio (1.95 to 2.07; P = 0.045) and number of abnormal forms of microsporidia (P < 0.01). Fecal TNF-alpha level nonsignificantly decreased from 17.9 to 8.9 U/mL. There was apparent disruption of all stages of the life cycle of E. intestinalis. CONCLUSIONS: Thalidomide may be an effective therapy for
diarrhea and
weight loss from E. bieneusi. Thalidomide appears to be highly effective for oropharyngeal apthous ulcers in HIV- infected patients. However, there are limited data regarding the use of this drug for the treatment of HIV-associated idiopathic esophageal ulcer(s) (IEU). Twelve HIV- infected patients with esophageal symptoms and IEU as defined by previously proposed criteria were studied prospectively. Two of these patients had failed oral corticosteroid treatment, and two others had a previous history of IEU. Patients were treated with thalidomide (200 mg/day orally) for 28 days in an open label fashion. Clinical evaluation was performed weekly with endoscopic reexamination performed at the completion of treatment. After therapy, patients were followed clinically with endoscopy recommended for recurrent esophageal symptoms. Of the 12 treated patients, 11 (92%) had a complete symptomatic response; endoscopy in 11 patients at the completion of treatment showed 9 with complete ulcer healing, 1 partially healed, and 1 with no response. All responders were asymptomatic by day 28. The partial responder received an additional 1 month of thalidomide at 300 mg/day, resulting in complete endoscopic healing. The patient failing therapy received prednisone, but died prior to completing this therapy. On follow-up to 20 months, six patients have died with no recurrence of IEU. Three patients had relapse of IEU, two of whom had a prior history of multiple recurrences of IEU; both of these patients relapsed within 2 months of completing thalidomide treatment. The
drug was
well tolerated without significant side effects. Thalidomide appears to be
an
effective and well-tolerated alternative to prednisone for the treatment of
IEU. We review the efficacy, tolerability and safety of low-dose thalidomide in the treatment of refractory disfiguring rash in 16 patients with cutaneous manifestations of lupus. Rashes, which included discoid lupus erythematosus (DLE), subacute cutaneous lupus (SCLE), photosensitive malar rash and non-specific chronic erythema, were diagnosed on clinical grounds, supported by skin biopsy in 11/16 patients. Using starting doses of 50-100 mg/day, 7/16 (44%) patients gained complete or near- complete remission of skin disease and 6/16 (37%) partial remission. Three out of 16 patients failed to respond. Maximum benefit was achieved within 16 weeks in all patients. Doses of 25-50 mg/day were effective in maintaining response. Rapid relapse occurred in 6/8 (75%) patients following drug withdrawal, but the response to thalidomide in those requiring repeat courses appeared to be maintained. There was
no detectable improvement in systemic disease. One patient developed
symptoms of
mild peripheral neuropathy which resolved on drug withdrawal. Our experience
suggests that thalidomide is effective in the treatment of severe skin
manifestations
of lupus refractory to other treatment and can be used safely in specialist
rheumatological practice.
Thalidomide has recently been shown to antagonize basic fibroblast growth factor- induced angiogenesis in the rat corneal micropocket assay. We have investigated the effect of thalidomide on growth, radiosensitivity and metastasis in murine SCCVII and Lewis Lung tumors. We found that daily thalidomide administration (0.77 mmol/kg/day, i.p.) does not alter primary tumor growth of SCCVII or Lewis Lung tumors. However, thalidomide administration does reduce radiosensitivity of the Lewis Lung tumor, and increases its sensitivity to combined treatment with radiation and the bioreductive cytotoxin tirapazamine. These findings suggest that thalidomide is elevating tumor hypoxia in the Lewis Lung tumor, presumably via an anti-angiogenic mechanism. We also found that thalidomide administration reduces the incidence of lung metastases from primary Lewis Lung tumors. Thalidomide may therefore have utility in
the
management of solid tumors, especially when combined with drugs that are
selectively
toxic to cells at reduced oxygen tension (e.g. bioreductive cytotoxins).
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. BACKGROUND: Thalidomide is used for the symptomatic treatment of recurrent aphthous stomatitis (RAS). Some authors reported remissions, but this was not evaluated. OBJECTIVE: To evaluate the number of patients who could stop or reduce thalidomide treatment. METHODS: Twenty-five patients with RAS treated with thalidomide and followed during at least 1 year were retrospectively studied. RESULTS: Six patients could stop the treatment and further presented minor aphthae, 10 needed minimal daily doses of thalidomide and 7 did not respond to 100 mg daily. One patient was not evaluated because of an early side effect and one was lost to follow-up. CONCLUSION:
This study showed that a minority of patients responded and could stop
thalidomide
therapy whereas another group of patients could be maintained in remission
with low
doses of thalidomide which may represent a means to reduce the potentially
severe
side effects.
The Thalidomide Chronology First marketed as a sedative & for morning sickness. Never marketed in the US. Worldwide ban in 1961 Associated with phocomelia & other congenital abnormalities. Sheskin, 19651 Found thalidomide effective in erythema nodosum leprosum. Dose of 100 mg three to four times daily. From the ban until now Unapproved, illegal use. Bootleg/blackmarket supply. Compassionate use approval available in the US and Canada. Supplies from Carville, La. in the past, Celgene now. 1988 - WHO recommend Future indications Candidates are AIDS-related cachexia or aphthous ulcers,2 graft versus host disease, and recalcitrant discoid lupus erythematosus. Future developments Celgene and Andrulis are involved in on-going clinical trials with thalidomide. Celgene are working on developing related compounds with useful activity and fewer side effects. Use of thalidomide for ENL The WHO has stated that thalidomide is a treatment of choice for severe ENL and now the FDA has decided that the benefits of treatment with thalidomide outweigh the risks involved. ENL can be life threatening and may cause permanent nerve paralysis and disfigurement. Previously available treatments for severe ENL, corticosteroids and clofazimine are not very effective. Mild ENL has been successfully treated with aspirin, indomethacin, chloroquine or colchicine. If Celgene's claim that at least 90% of ENL patients respond to
thalidomide proves correct, does this raise the possibility of
thalidomide
being used for all cases of ENL? More than 20 clinical trials are underway and the drug is also
supplied on an
emergency use basis or investigator IND basis for over 30
conditions. Currently
the dermatologic conditions include Behcet's disease, prurigo
nodularis, discoid
lupus erythematosus, pyoderma gangrenosum, erythema multiforme,
Jessner's
lymphatic infiltration, pompholyx, scleroderma, urticaria, bullous
pemphigoid
and cutaneous sarcoidosis.3 The mechanism by which thalidomide reduces the elevated levels of
tumor
necrosis factor-alpha (TNF-alpha) associated with ENL is yet to be
understood.4 Thalidomide has other immunopharmacologic actions
which are
under investigation.4 Dr. J. McGuire, Stanford
(Advisory Committee Chairman)7 Contraception Female patients will have to agree to use two forms of birth control, to undergo ongoing pregnancy tests and to participate in monthly surveys. Patients who have irregular menstrual periods, vaginal bleeding or missed periods may need more frequent pregnancy tests. Males will have to agree to use condoms and to complete surveys every three months. They must abstain from sexual intercourse or use a condom during intercourse while, and for one month after, taking thalidomide. It is not known if thalidomide is present in semen.8 A female patient must immediately stop taking thalidomide if she: Has a late or irregular period. Stops practicing abstinence. Stops using birth control. Thinks that she is pregnant. Does become pregnant.9 Supply of thalidomide Thalomid™ will possibly be available commercially in the first half of this year. The projected cost of a 50 mg capsule is US$6, meaning that daily treatment of ENL (100-200 mg per day) will cost approximately US$12-24. Patients will only get a 28 day supply; subsequent supply requires a new prescription. Adverse effects The neuropathy generally occurs following chronic use over a period of months but reports following relatively short-term use also exist. In some cases, the nerve damage has proved irreversible even after treatment with the drug is discontinued. Individual susceptibilities, with possible genetic predisposition, seem to be more important than daily dose and duration of therapy.10 Patients should be examined for early signs of neuropathy at monthly
intervals for the first three months.3 Symptoms of nerve damage include numbness,
tingling or pain in the arms, hands, legs and feet. Patients should be warned
of this side effect, and understand that they must stop thalidomide immediately if
paresthesias develop.11 To detect asymptomatic neuropathy, consider
measuring sensory nerve action potential (SNAP) at baseline and every six
months. If symptoms develop, stop thalidomide immediately and only restart
therapy if the neuropathy completely resolves. Future Possibilities References 2.Jacobsen JM, Greenspan JS, Spritzler J et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 1997; 336: 1487-1493. 3.David Stirling, Celgene. Personal communication. January, 1997. 4.Calderon P, Anzilotti M, Phelps R. Thalidomide in dermatology. New indications for an old drug. Int J Dermatol 1997; 36: 881-887. 5.Kaplan G. quoted by Blaney C., Second thoughts about thalidomide. Medical Sciences Bulletin, originally published in NCRR Reporter, November/December 1995. 6.Lumpkin M., Deputy Director FDA's Center for Drug Evaluation speaking at a meeting of the FDA Advisory Committee, quoted in Reuters Medical News. 7.McGuire J. Personal communication. October, 1997. 8.Thalidomide: Important patient information. US FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/news/thalidomide.htmL 9.Burkholz H. Giving thalidomide a second chance. FDA Consumer Magazine 1997: September-October. 10.Ochonisky SO, Verroust J, Basuji-Garin S. et al. Arch Dermatol 1994;130: 66-69. 11.Powell RJ, Garner-Medwin JMM. Postgrad Med J 1994; 70: 901-904. 12.Dubertret L. Personal communication. October, 1997. Such drug products may not be legally marketed
until the firm has satisfied the identified deficiencies, as well as any other
requirements that may be imposed by the FDA, and has been notified in
writing that the application has been approved. - The United States Food and Drug Administration has granted marketing clearance to Celgene Corp.'s Thalomid(TM) (thalidomide) for the treatment of erythema nodosum leprosum (ENL), a severe and debilitating condition associated with leprosy. Celgene licensed rights to thalidomide from The Rockefeller University in 1992 and began developing the drug for a range of potential indications. These include AIDS related, dermatological and cancer related conditions. In order to support the safe and appropriate use of the drug, due to concern about the teratogenic potential of thalidomide in humans when the drug is take during pregnancy, Celgene has developed a unique and comprehensive patient, physician and pharmacist education and distribution system to be called the System for Thalidomide Education and Prescribing Safety (STEPS). Major Components of the STEPS Program include: -- Physicians prescribing Thalomid and pharmacists dispensing the drug will register and receive educational materials explaining risks and pregnancy prevention methods, as well as expected side effects of therapy. -- All females who are candidates for Thalomid therapy will be required to undergo pregnancy testing before starting treatment and periodically thereafter. -- Women will also be required to use effective birth control while taking the
drug. -- Before a prescription is filled, a copy of the informed consent form st be presented at a pharmacy pre-registered to dispense Thalomid. -- Persons using Thalomid will be required to participate in a patient survey
designed to determine compliance with the STEPS program and any situations
involving pregnancy. ====================================================================== |
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Produced by Dr. José Lapenta R.
Dermatologist
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