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****** DATA-MEDICOS *********

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LA TALIDOMIDA, EL REGRESO, THE THALIDOMIDE'S COME BACK 

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***** DERMAGIC-EXPRESS No 9 *****

****** 23 OCTUBRE DE 1.998 ******* 

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EDITORIAL:

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Hola amigos dermágicos, en la edición de hoy La TALIDOMIDA, un medicamento que en los años 50 causó una generación de niños con malformaciones. 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 dia, 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. 

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DERMAGIC/EXPRESS(9)

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LA TALIDOMIDA, EL REGRESO / THE THALIDOMIDE'S COME BACK

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1.) The thalidomide tragedy in Germany: the end of a historic

medicolegal trial.

2.) Thalidomide's long shadow [editorial]

3.) Damages awarded for thalidomide children.

4.) Normal child after maternal thalidomide ingestion in critical

period of pregnancy.

5.) Another chance for thalidomide?

6.) Crossover study of thalidomide vs placebo in Jessner's

lymphocytic infiltration of the skin.

7.) Treatment of cutaneous and pulmonary sarcoidosis with thalidomide.

8.) Thalidomide as treatment of refractory aphthous ulceration

related to human immunodeficiency virus infection.

9.) Amniotic band sequence in child of thalidomide victim [letter;

comment]

10.) Chronic cutaneous lupus erythematosus treated with thalidomide.

11.) Remission of Langerhans cell histiocytosis with thalidomide

treatment [letter]

12.) Thalidomide for the treatment of chronic graft-versus-host

disease [see comments]

13.) Thalidomide's effectiveness in erythema nodosum leprosum is

associated with a decrease in CD4+ cells in the peripheral blood.

14.) Lupus erythematosus profundus with partial C4 deficiency

responding to thalidomide.

15.) Pyoderma gangrenosum associated with Behcet's disease: treatment with thalidomide.

16.) Thalidomide in type-2 lepra reaction--a clinical experience.

17.) Combination thalidomide and cyclosporine for cardiac allograft rejection. Comparison with combination methylprednisolone and cyclosporine.

18.) Treatment of refractory rheumatoid arthritis--the thalidomide

experience.

19.) Successful treatment with thalidomide of acute graft-versus-host

20.) Thalidomide. A surprising recovery.

21.) Thalidomide: a novel therapy for microsporidiosis.

22.) A prospective trial of thalidomide for the treatment of

HIV-associated idiopathic esophageal ulcers.

23.) Thalidomide in the treatment of the cutaneous manifestations of lupus erythematosus: experience in sixteen consecutive patients.

24.) The effect of thalidomide on experimental tumors and metastases.

25.) Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-hostdisease.

26.) Thalidomide and recurrent aphthous stomatitis: a follow-up study.

27.) THALIDOMIDE, the product.

28.) FDA Clears Thalidomide For Leprosy

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1.) TI - The thalidomide tragedy in Germany: the end of a historic

medicolegal trial.

SO - N Engl J Med 1971 Mar 4;284(9):481-2

AU - Curran WJ

===================================================================

===================================================================

2.) TI - Thalidomide's long shadow [editorial]

SO - Br Med J 1976 Nov 13;2(6045):1155-6

MJ - Drug Industry; Drug Therapy [adverse effects]

===================================================================

===================================================================

3.)TI - Damages awarded for thalidomide children.

SO - Lancet 1969 Aug 9;2(615):331-2

AU - Whicher H

MJ - Abnormalities, Drug-Induced [etiology]; Jurisprudence; Thalidomide

[adverse effects]

===================================================================

===================================================================

4.) TI - Normal child after maternal thalidomide ingestion in critical

period of pregnancy.

SO - Lancet 1970 Feb 7;1(641):275-7

AU - Pembrey ME; Clarke CA; Frais MM

MJ - Thalidomide [adverse effects]

MN - Child; Gestational Age; Pregnancy

===================================================================

===================================================================

5.) TI - Another chance for thalidomide?

SO - Lancet 1966 Apr 30;1(444):981-2

AU - Vladutiu A

MJ - Encephalomyelitis, Allergic [immunology]; Encephalomyelitis;

Immunosuppressive Agents [therapeutic use]; Thalidomide [therapeutic use]

===================================================================

===================================================================

6.) TI - Crossover study of thalidomide vs placebo in Jessner's

lymphocytic infiltration of the skin.

===================================================================

SO - Arch Dermatol 1995 Sep;131(9):1032-5

AU - Guillaume JC; Moulin G; Dieng MT; Poli F; Morel P; Souteyrand P;

Bonnetblanc JM; Claudy A; Daniel F; Vaillant L; et al

AD - Dermatology Service, Hopital Henri Mondor, Creteil, France.

MJ - Skin Diseases [drug therapy]; Thalidomide [therapeutic use]

MN - Adult; Cross-Over Studies; Double-Blind Method; Middle Age;

Prospective Studies; Thalidomide [adverse effects]

MT - Female; Human; Male; Support, Non-U.S. Gov't

PT - CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED

CONTROLLED TRIAL

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.

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7.) TI - Treatment of cutaneous and pulmonary sarcoidosis with thalidomide.

===================================================================

SO - J Am Acad Dermatol 1995 May;32(5 Pt 2):866-9

AU - Carlesimo M; Giustini S; Rossi A; Bonaccorsi P; Calvieri S

AD - Department of Dermatology, University of Rome La Sapienza, Italy.

MJ - Sarcoidosis, Pulmonary [drug therapy]; Sarcoidosis [drug therapy];

Skin Diseases [drug therapy]; Thalidomide [therapeutic use]

MN - Aged; Middle Age; Sarcoidosis, Pulmonary [complications]; Sarcoma,

Kaposi's [complications]; Skin Diseases [complications]; Skin Neoplasms

[complications]

MT - Case Report; Female; Human

PT - JOURNAL ARTICLE

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.

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8.) TI - Thalidomide as treatment of refractory aphthous ulceration

related to human immunodeficiency virus infection.

===================================================================

SO - Clin Infect Dis 1995 Feb;20(2):250-4

AU - Paterson DL; Georghiou PR; Allworth AM; Kemp RJ

AD - Infectious Diseases Unit, Royal Brisbane Hospital, Herston,

Queensland, Australia.

MJ - HIV Infections [complications]; HIV-1; Stomatitis, Aphthous [drug

therapy]; Thalidomide [therapeutic use]

MN - Adult; Middle Age; Recurrence; Retrospective Studies; Stomatitis,

Aphthous [etiology]; Thalidomide [adverse effects]

MT - Human; Male

PT - CLINICAL TRIAL; JOURNAL ARTICLE

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.

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9.) TI - Amniotic band sequence in child of thalidomide victim [letter;

comment]

CM - Comment on: BMJ 1994 Jun 18; 308(6944):1635-6; Comment on: BMJ 1994

Aug 13; 309(6952):477

SO - BMJ 1994 Nov 26;309(6966):1442

AU - Tenconi R; Clementi M; Notari L; Lo Vasco VR

MJ - Amniotic Band Syndrome [etiology]; Extremities [abnormalities]; Hand

Deformities, Congenital [etiology]; Prenatal Exposure Delayed Effects;

Thalidomide [adverse effects]

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10.) TI - Chronic cutaneous lupus erythematosus treated with thalidomide.

SO - Arch Dermatol 1993 Dec;129(12):1548-50

AU - Holm AL; Bowers KE; McMeekin TO; Gaspari AA

AD - University of Rochester (NY) Medical Center.

MJ - Lupus Erythematosus, Discoid [drug therapy]; Scalp Dermatoses [drug

therapy]; Thalidomide [therapeutic use]

MN - Adult; Alopecia [drug therapy]; Prednisone [administration & dosage]

[therapeutic use]; Thalidomide [administration & dosage]

MT - Case Report; Female; Human

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11.) TI - Remission of Langerhans cell histiocytosis with thalidomide

treatment [letter]

SO - Clin Exp Dermatol 1993 Sep;18(5):487

AU - Misery L; Larbre B; Lyonnet S; Faure M; Thivolet J

MJ - Histiocytosis, Langerhans-Cell [drug therapy]; Thalidomide

[therapeutic use]

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12.) TI - Thalidomide for the treatment of chronic graft-versus-host

disease [see comments]

===================================================================

CM - Comment in: N Engl J Med 1992 Sep 3; 327(10):735

SO - N Engl J Med 1992 Apr 16;326(16):1055-8

AU - Vogelsang GB; Farmer ER; Hess AD; Altamonte V; Beschorner WE; Jabs

DA; Corio RL; Levin LS; Colvin OM; Wingard JR; et al

AD - Department of Oncology, Johns Hopkins University School of Medicine,

Baltimore, Md.

MJ - Graft vs Host Disease [drug therapy]; Immunosuppressive Agents

[therapeutic use]; Thalidomide [therapeutic use]

MN - Adolescence; Adult; Bone Marrow Transplantation [adverse effects];

Child; Chronic Disease; Graft vs Host Disease [mortality];

Immunosuppressive Agents [administration & dosage] [adverse effects];

Infection [complications]; Middle Age; Thalidomide [administration &

dosage] [adverse effects]

MT - Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

PT - CLINICAL TRIAL; JOURNAL ARTICLE

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.

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13.) TI - Thalidomide's effectiveness in erythema nodosum leprosum is

associated with a decrease in CD4+ cells in the peripheral blood.

===================================================================

SO - Lepr Rev 1992 Mar;63(1):5-11

AU - Shannon EJ; Ejigu M; Haile-Mariam HS; Berhan TY; Tasesse G

AD - Pharmacology Research Department, G.W. Long Hansen's Disease Center,

Carville, La 70721.

MJ - CD4-CD8 Ratio; Erythema Nodosum [drug therapy]; Leprosy, Lepromatous

[drug therapy]; Thalidomide [therapeutic use]

MN - Adult; Erythema Nodosum [immunology]; Leprosy, Lepromatous [immunology]

MT - Human; Male; Support, Non-U.S. Gov't

PT - JOURNAL ARTICLE

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.

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14.) TI - Lupus erythematosus profundus with partial C4 deficiency

responding to thalidomide.

===================================================================

SO - Br J Dermatol 1991 Jul;125(1):62-7

AU - Burrows NP; Walport MJ; Hammond AH; Davey N; Jones RR

AD - St. John's Dermatology Centre, St. Thomas' Hospital, London, U.K.

MJ - Complement 4 [deficiency]; Panniculitis, Lupus Erythematosus [genetics]

MN - Adolescence; Complement 4a [deficiency]; Complement 4b [deficiency];

Panniculitis, Lupus Erythematosus [drug therapy] [pathology]; Pedigree;

Skin [pathology]; Thalidomide [therapeutic use]

MT - Case Report; Female; Human; Support, Non-U.S. Gov't

PT - JOURNAL ARTICLE

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.

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15.) TI - Pyoderma gangrenosum associated with Behcet's disease: treatment

with thalidomide.

SO - J Am Acad Dermatol 1990 Nov;23(5 Pt 1):941-4

AU - Rustin MH; Gilkes JJ; Robinson TW

AD - Department of Dermatology, Royal Free Hospital, London, England.

MJ - Behcet's Syndrome [complications]; Leg Ulcer [pathology]; Pyoderma

[complications]; Thalidomide [therapeutic use]

MN - Adult; Gangrene; Leg Ulcer [drug therapy]; Prednisolone

[administration & dosage] [therapeutic use]; Pyoderma [drug therapy]

[pathology]; Recurrence

===================================================================

16.)TI - Thalidomide in type-2 lepra reaction--a clinical experience.

===================================================================

SO - Indian J Lepr 1990 Jul-Sep;62(3):316-20

AU - Jadhav VH; Patki AH; Mehta JM

AD - Dr. Bandorawala Leprosy Hospital, Pune.

MJ - Leprosy, Lepromatous [drug therapy]; Thalidomide [therapeutic use]

MN - Adolescence; Adult; Anti-Inflammatory Agents, Non-Steroidal

[therapeutic use]; Drug Therapy, Combination; Middle Age; Thalidomide

[adverse effects]

MT - Human; Male

PT - CLINICAL TRIAL; JOURNAL ARTICLE

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.

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17.) TI - Combination thalidomide and cyclosporine for cardiac allograft

rejection. Comparison with combination methylprednisolone and cyclosporine.

===================================================================

SO - Transplantation 1990 Jan;49(1):20-5

AU - Tamura F; Vogelsang GB; Reitz BA; Baumgartner WA; Herskowitz A

AD - Department of Cardiovascular Surgery, Johns Hopkins Medical

Institutions, Baltimore, Maryland 21205.

MJ - Cyclosporins [administration & dosage]; Graft Rejection [drug

effects]; Heart Transplantation; Methylprednisolone [administration &

dosage]; Thalidomide [administration & dosage]

MN - Drug Therapy, Combination; Immunosuppression; Rats, Inbred Lew; Rats;

Transplantation, Homologous

MT - Animal; Comparative Study; Male; Support, Non-U.S. Gov't; Support,

U.S. Gov't, P.H.S.

PT - JOURNAL ARTICLE

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.

===================================================================

18.) TI - Treatment of refractory rheumatoid arthritis--the thalidomide

experience.

===================================================================

SO - J Rheumatol 1989 Feb;16(2):158-63

AU - Gutierrez-Rodriguez O; Starusta-Bacal P; Gutierrez-Montes O

AD - Department of Medicine, Facultad de Salud, Universidad del Valle,

Hospital Universitario del Valle, Evaristo Garcia, Cali, Colombia.

MJ - Arthritis, Rheumatoid [drug therapy]; Thalidomide [therapeutic use]

MN - Adult; Aged; Edema [chemically induced]; Middle Age; Pain; Sleep

Stages [drug effects]; Thalidomide [adverse effects]

MT - Female; Human; Male

PT - JOURNAL ARTICLE

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.

===================================================================

19.) TI - Successful treatment with thalidomide of acute graft-versus-host

disease after bone-marrow transplantation [letter]

SO - Lancet 1988 Jan 16;1(8577):117

AU - Lim SH; McWhannell A; Vora AJ; Boughton BJ

MJ - Bone Marrow Transplantation; Bone Marrow [transplantation]; Graft vs

Host Disease [drug therapy]; Thalidomide [therapeutic use]

===================================================================

20.) Thalidomide. A surprising recovery.

===================================================================

Stirling D; Sherman M; Strauss S

Celgene Corporation, Warren, N.J., USA.

J Am Pharm Assoc (Wash) (UNITED STATES) May-Jun 1997 NS37 (3) p306-13

ISSN: 

1086-5802

Language: ENGLISH

Document Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL 

Journal Announcement: 9710

Subfile: INDEX MEDICUS

The epidemic of birth defects in Europe in the early 1960s attributed to 

thalidomide led to stringent and unprecedented drug safety requirements in

many 

countries. No definitive mechanism of action has been determined for the

biological 

activities associated with thalidomide. Food and Drug Administration and 

congressional concerns about the handling of clinical investigations of

thalidomide 

led to sweeping new regulations for clinical trials. Thalidomide is

currently being 

used clinically to treat such conditions as cachexia associated with HIV

and cancer, 

mycobacterial disease, and autoimmune diseases. (38 References)

===================================================================

21.) Thalidomide: a novel therapy for microsporidiosis.

===================================================================

Sharpstone D; Rowbottom A; Francis N; Tovey G; Ellis D; Barrett M; 

Gazzard B 

Department of HIV/GUM, Chelsea and Westminster Hospital, London, England.

Gastroenterology (UNITED STATES) Jun 1997 112 (6) p1823-9 ISSN:

0016-5085

Language: ENGLISH

Document Type: CLINICAL TRIAL; JOURNAL ARTICLE 

Journal Announcement: 9709

Subfile: AIM; 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.

===================================================================

22.) A prospective trial of thalidomide for the treatment of

HIV-associated idiopathic esophageal ulcers.

===================================================================

Alexander LN; Wilcox CM

Department of Medicine, Emory University School of Medicine, Atlanta,

Georgia, USA.

AIDS Res Hum Retroviruses (UNITED STATES) Mar 1 1997 13 (4) p301-4

ISSN: 0889-

2229

Language: ENGLISH

Document Type: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED

TRIAL 

Journal Announcement: 9709

Subfile: INDEX MEDICUS

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.

===================================================================

23. Thalidomide in the treatment of the cutaneous manifestations of lupus erythematosus: experience in sixteen consecutive patients.

===================================================================

Stevens RJ; Andujar C; Edwards CJ; Ames PR; Barwick AR; Khamashta MA;

Hughes GR

Department of Rheumatology, Rayne Institute, St Thomas Hospital, London.

Br J Rheumatol (ENGLAND) Mar 1997 36 (3) p353-9 ISSN: 0263-7103

Language: ENGLISH

Document Type: JOURNAL ARTICLE 

Journal Announcement: 9707

Subfile: AIM; INDEX MEDICUS

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.

===================================================================

24.) The effect of thalidomide on experimental tumors and metastases.

===================================================================

Minchinton AI; Fryer KH; Wendt KR; Clow KA; Hayes MM

Department of Medical Biophysics, BC Cancer Research Centre, Vancouver,

Canada.

Anticancer Drugs (ENGLAND) May 1996 7 (3) p339-43 ISSN: 0959-4973

Language: ENGLISH

Document Type: JOURNAL ARTICLE 

Journal Announcement: 9707

Subfile: INDEX MEDICUS

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).

===================================================================

25.) Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-hostdisease.

===================================================================

Chao NJ; Parker PM; Niland JC; Wong RM; Dagis A; Long GD; Nademanee AP;

Negrin RS; 

Snyder DS; Hu WW; Gould KA; Tierney DK; Zwingenberger K; Forman SJ; Blume KG

Department of Medicine, Stanford University Medical Center, CA 94305, USA.

Biol Blood Marrow Transplant (UNITED STATES) May 1996 2 (2) p86-92

ISSN: 1083-

8791

Language: ENGLISH

Document Type: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED

TRIAL 

Journal Announcement: 9706

Subfile: INDEX MEDICUS

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.

===================================================================

26.) Thalidomide and recurrent aphthous stomatitis: a follow-up study.

===================================================================

Bonnetblanc JM; Royer C; Bedane C

Department of Dermatology, CHRU Dupuytren, Limoges, France.

Dermatology (SWITZERLAND) 1996 193 (4) p321-3 ISSN: 1018-8665

Language: ENGLISH

Document Type: JOURNAL ARTICLE 

Journal Announcement: 9705

Subfile: INDEX MEDICUS

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.

================================================================

27.) Thalidomide, the product.// FROM THE SKIN THERAPY LETTER

===================================================================

On Friday, September 19, 1997 the FDA indicated to the Celgene

Corporation that thalidomide, Thalomid® has been designated as

approvable (see explanation below) for the treatment of cutaneous

manifestations of erythema nodosum leprosum (ENL). In this condition

there are no good alternative treatments to thalidomide. ENL is a

severe and painful complication for approximately half of all leprosy

patients, affecting about two million people worldwide.

The Thalidomide Chronology

Introduced in the late 1950's

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

WHO's treatment of choice for severe ENL. Based on the results of

a double-blind, multi-centered trial. 

Late 1997 - first US approval nears

FDA Advisory Panel September 5, 1997 recommends the approval of

thalidomide for ENL. 

FDA, September 19, 1997 designates thalidomide as approvable for

the treatment of cutaneous manifestations of ENL. 

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?

Dr. Stuart Maddin, Editor

Other uses of thalidomide

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

Mechanism of action

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 

Thalidomide prevents the immune system from overreacting to disease

and harming the body. Among its known modes of action is the

inhibition

of production of cytokine TNF-alpha.

Dr Kaplan, Rockefeller University.5

Precautions Restricted distribution Celgene designed and has submitted a

restricted distribution proposal (System for Thalidomide Education and

Prescribing Safety (S.T.E.P.S.) to the FDA. The objective of the S.T.E.P.S. program is

to help insure that fetal exposure to thalidomide occurs with the lowest

possible incidence. This comprehensive program will be directed to physicians,

pharmacists, and patients, both male and female. It will require all physicians

and pharmacies to register in order to prescribe or dispense Thalomid™ (thalidomide) and all patients to complete an informed consent process and

participate in a mandatory and confidential surveillance registry.

There are precedents for restricted distribution of a drug,

isotretinoin,clozapine and fentanyl oralet have all been marketed successfully this

way, and thalidomide when approved, will have more restrictions on it than any drug ever sold in the U.S.

M. Lumpkin, FDA's Centre for Drug Evaluation6

Off-label use Some members of the FDA's Advisory panel have suggested

that off-label use for other illnesses be prohibited; however the

distribution system is designed to cover any use of the drug.

"We need to make this system as leak-proof as possible."

Dr. J. McGuire, Stanford 

(Advisory Committee Chairman)7

Informed consent waivers Patients and physicians will have to sign detailed

informed consent waivers.

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 most common adverse effects are drowsiness, rash and constipation.

Peripheral neuropathy

Peripheral neuropathy occurs in less than 1% of ENL patients

treated with thalidomide, despite long-term treatment, pre-existing

neuropathies, or use in patients who are receiving other medications known to be associated with neuropathies.3 Neuropathy is more common (between 21% and 50%) in AIDS

patients. 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.

Birth defects

At the meeting of the FDA Advisory Committee, a spokesman for the5,000

individuals with birth defects caused by thalidomide who are still

living, was saddened at the prospect of potential approval but said that the

group preferred regulation to unmonitored use of black market supplies. Celgene said

that there have been no birth defects reported so far among the 5,000 ENL

patients who have received thalidomide, either through clinical trials or on an

emergency basis.

Professor Louis Dubertret of Paris is of the opinion that the French

regulatory controls for distribution and use have made thalidomide a very safe

drug for the very limited number of patients receiving it.

Future Possibilities

Molecular manipulation has uncovered other thalidomide-related compounds

which inhibit TNF-alpha production more efficiently than

thalidomide, and cause fewer side effects in animals.5 Celgene's first compound entered Phase1 clinical study in 1997.3 The goal, a non-teratogenic compound, with equal or

greater immunomodulating potential than thalidomide, offers the

exciting possibility of new and relatively safe compounds which may prove effective in treating diseases at present resistant to currently available therapies. Thalidomide itself has a range of interesting and potentially useful immuno-pharmacologic actions4 and after further study and sensible precautions as to its use, has a clear potential as a future immunomodulator.

References

1.Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Phar

Therap 1965; 6: 303. 

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.htm. 

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. 

Approvable Status: An approvable letter indicates that FDA is prepared

to approve the application upon the satisfaction of conditions specified in

the approvable letter. 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.

===========================================================

28.) FDA Clears Thalidomide For Leprosy

===========================================================

WARREN, NJ -- July 16, 1998 - 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.

-- Men using the drug will be required to use condoms when having sexual

relations with women.

-- All candidates for Thalomid therapy will be provided with counselling by the

physician and comprehensive multicultural and multilingual educational material

clearly explaining the risks of use. 

-- Patients will be required to sign an informed consent form after an

explanation of the risks of Thalomid use by the physician.

-- 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.

-- Patients will be instructed never to share the drug with other persons,

including friends or relatives with the same symptoms for which Thalomid was

prescribed.

-- Thalomid packaging will contain clear and prominent warnings about the

risks associated with use. Prescriptions for Thalomid will be no more than a 28

day supply with no automatic renewals.

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DATA-MEDICOS/DERMAGIC-EXPRESS No (8) 23/10/98 DR. JOSE LAPENTA R. DERMATOLOGO

======================================================================