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Thalidomide

Thalidomide is a drug that was sold during the late 1950s and 1960s as a sleeping aid and to pregnant women as an antiemetic to combat morning sickness and other symptoms. It was synthesized in West Germany in 1953 and marketed by the Stolberg-near-Aachen-based pharmaceutical company Grünenthal from October 1, 1957 to 1961, mainly in Germany and Britain. It was available in around fifty countries, although not in the United States, under at least forty names (such as Talimol, Kevadon, Nibrol, Sedimide, Quietoplex, Contergan, Neurosedyn, etc.). more...

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It was later (1960–61) found to be teratogenic in fetal development, most visibly as a cause of amelia or phocomelia, especially if taken during the first 25 to 50 days of pregnancy. Around 15,000 fetuses were damaged by thalidomide, of whom about 12,000 in 46 countries were born with birth defects, with only 8,000 of them surviving past the first year of life. Most of these survivors are still alive, nearly all with disabilities caused by the drug. In 2003, a World Health Organization newsletter cited evidence that the disabilities and deformities in many thalidomide survivors may be passed on to the survivor's own children through DNA, but many discount this as scientifically unfounded. Those deformed by thalidomide are sometimes referred to (or self-described) as thalidomiders or the derogatory abbreviative, "Flids".

Thalidomide was banned for its initial intended use as sedative. However, it has been found to be effective for other indications such as for leprosy and multiple myeloma. It is now marketed by Celgene as Thalomid with standard warnings for pregnant women to avoid taking it.

The thalidomide tragedy

Thalidomide had passed safety tests performed on animals, primarily because the proper tests — particularly those involving pregnant animals — had not been done. A court trial revealed that some tests were either conducted inadequately, or the results were faked.

There is also some evidence that the tests were carried out on a particular isomer of the drug, which forms a racemic mixture in the body. One element of this mixture has the intended beneficial action, while the other creates the horrific side effects.

The failure of these tests to discover the drug's disastrous consequences highlighted the inadequacy of testing methodologies in use at that time. This resulted in a dramatic increase in animal testing across a broad range of species in varying stages of pregnancy and lifecycle. In fact, later tests did demonstrate that administering thalidomide to rabbits and mice produces characteristic deformities in the offspring, although thalidomide has no effect on pregnant rats' offspring, (see Blake DA, Gordon GB, Spielberg SP. The role of metabolic activation in thalidomide teratogenesis. Teratology 1982;25(2):28A-29A.). If adequate testing had been done, thalidomide would never have been approved for pregnant women. Some opponents of animal testing still incorrectly cite thalidomide as an example of the ineffectiveness of such testing.

In 1960, Chemie Grünenthal decided to expand into the United States, and applied to the Food and Drug Administration for approval to sell the drug. This approval was not expected to be controversial, and the case was given to the agency's newest reviewer, Frances Oldham Kelsey. Kelsey had previously done animal toxicity research (including effects in pregnancy), and refused to clear thalidomide for sale until she obtained better documentation of its effects, especially in light of some unusual neurological side effects being reported in Britain. In fact, the testing had not been performed adequately, and satisfactory documentation was not forthcoming.

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Irinotecan and thalidomide in treating patients with advanced solid tumors - Clinical Trial Review
From Journal of Drugs in Dermatology, 8/1/03

Sponsored by: University of Chicago Cancer Research Center and National Cancer Institute (NCI)

RATIONALE: Thalidomide may stop the growth of cancer by stopping blood flow to the tumor. Drugs used in chemotherapy such as irinotecan use different ways to stop tumor ceils from dividing so they stop growing or die. Combining thalidomide with irinotecan may kill more tumor cells.

PURPOSE: Randomized phase I trial to study the effectiveness of combining thalidomide with irinotecan in treating patients who have metastatic or unresectable solid tumors.

Study Type: Interventional

Study Design: Treatment

OBJECTIVES:

* Determine whether thalidomide alters the pharmacokinetics of irinotecan in patients with advanced solid tumors.

* Determine whether irinotecan alters the pharmacokinetics of thalidomide in these patients.

* Determine the toxicity of this regimen in these patients.

* Determine the observed antitumor response in patients treated with this regimen.

OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive irinotecan IV over 90 minutes on days 1 and 22 and oral thalidomide once daily on days 15-28.

* Arm II: Patients receive irinotecan as in arm I and oral thalidomide once daily on days -6 to 7. All patients undergo disease reevaluation at 6 weeks. Patients with stable or responsive disease may receive additional courses comprising irinotecan IV on day 1 and oral thalidomide once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Ages eligible for study: 18 years and above, both genders

Inclusion Criteria:

* Histologically confirmed malignant solid tumor

* Metastatic or unresectable

* Standard curative or palliative therapy is no longer effective or does not exist

* Measurable or assessable disease

* No uncontrolled brain metastases

* Patients with brain metastases are eligible provided the following are true:

* Stable neurologic status

* At least 4 weeks since prior steroids or anticonvulsants

* No neurologic dysfunction that would confound evaluation

Patient Characteristics:

* Performance status

* Karnofsky 70-100%

Life expectancy

* More than 12 weeks

Hematopoietic

* WBC at least 3,000/[mm.sup.3]

* Absolute neutrophil count at least 1,500/[mm.sup.3]

* Platelet count at least 100,000/[mm.sup.3]

Hepatic

* Bilirubin normal

* AST and ALT no greater than 2.5 times upper limit of normal

Renal

* Creatinine normal OR

* Creatinine clearance at least 60 mL/min

Cardiovascular

* No symptomatic congestive heart failure

* No unstable angina pectoris

* No cardiac arrhythmia

Gastrointestinal

* No history of inflammatory bowel disease requiring therapy

* NO chronic diarrhea syndromes

* No paralytic ileus

Other

* Not pregnant or nursing

* Negative pregnancy test

* Fertile female patients must use 2 forms of effective contraception, including 1 highly effective method, for at least 4 weeks before, during, and for 4 weeks after study participation

* Male patients must use effective barrier contraception during and for 4 weeks after study participation

* No prior allergic reaction attributed to compounds of similar chemical or biological composition to study drugs

* No uncontrolled seizure disorder

* No other concurrent uncontrolled illness that would preclude study participation

* No psychiatric illness or social situation that would preclude study compliance

* No ongoing or active infection

* No significant traumatic injury within the past 28 days

* No serious, nonhealing wounds or ulcers

* No bone fractures

* No preexisting peripheral neuropathy grade 2 or greater

PRIOR CONCURRENT THERAPY:

Biologic therapy

* At least 4 weeks since prior biologic therapy

Chemotherapy

* At least 4 weeks since prior chemotherapy (6 weeks for nitrosources or mitomycin)

Radiotherapy

* At least 4 weeks since prior radiotherapy

Surgery

* More than 28 days since prior major surgical procedure or open biopsy

Other

* At least 4 weeks since prior investigational therapy

* No concurrent combination antiretroviral therapy for HIV-positive patients

* No other concurrent investigational or commercial agents or therapies for the malignancy

Location and Contact Information

University of Chicago Cancer Research Center, Chicago, Illinois, 60637, United States; Mark J. Ratain, MD Study Chair, University of Chicago Cancer Research Center Tel: 773-702-4400

Illinois

A total of 12 patients (6 per treatment arm) will be accrued for this study.

Study ID Numbers CDR0000304517; UCCRC-12044B; NCI-5814

NLM Identifier NCT00062127

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