New clinical uses for thalidomide
Thalidomide (reaction stop Thalidomide)
Chemical structure: Glutamic acid derivative with two spin isomers under physiological ph conditions – R (right-handed) and S (left-handed)
R-configuration – sedative effect
S-configuration – teratogenic related
Pharmacokinetics
1.After 200mg oral dose, the plasma peak concentration is 0.8~1.4ug/ml in healthy people.
2.The average peak concentration is 4.4 hours.
3.The absorption half-life is about 1.7 hours.
4.Exclusion half-life is 4–28, average 8.7 hours or so
Historical review
It was first synthesized in 1954 in the former Federal Republic of Germany and marketed in Germany in 1956, where it was widely used as a sedative and to prevent pregnancy vomiting.
▪ In 1960, doctors in Europe began to notice a significant increase in the birth rate of malformed babies in the region.
In 1961, the product was recalled from the world market and banned from the market, and about 15,000 babies were already affected worldwide.
▪ Officially withdrawn from the market in 1963. Regulations leading to trials of new drugs were born!
▪ In 1965, it was accidentally discovered that Reactive Stop was effective in reducing skin symptoms in patients with erythema nodosum leprosum.
▪ In 1991 it was found to have an inhibitory effect on tumor necrosis factor (TNF-alpha)?a———– anti-inflammatory effect
▪ It was found to have anti-angiogenic effects in 1994?a?a————————– antitumor effects
Pharmacological effects of thalidomide
1.Anti-angiogenic effect: used in the treatment of anti-tumor and hematologic diseases
2, immunomodulatory effect (anti-inflammatory effect): used in the treatment of rheumatic immune diseases, skin diseases
3, central nervous system inhibitory effect (sedative effect): hypnotic, analgesic, antiemetic, anti-anxiety, anti-anxiety.
The main means of treating tumors.
1.Local treatment: surgery, radiotherapy
2.Systemic treatment: chemotherapy, immunotherapy, molecular targeting therapy (EGFR/VEGF)
Inhibition of tumor angiogenesis has become a new way of tumor treatment.
Mechanism of anti-tumor angiogenic drugs
Direct anti-tumor angiogenic drugs are characterized by
1, low toxicity
2, immature blood vessels in tumors, sensitive to drugs
3.Amplification effect
4.Stable genetic traits of endothelial cells, low chance of drug resistance
5.Synergistic effect with radiotherapy and chemotherapy
Thalidomide is used in the treatment of anti-tumor.
Glioma Renal cell carcinoma Intestinal cancer Liver cancer Lung cancer Malignant melanoma Prostate cancer Breast cancer Lymphoma
End-of-life treatment of tumors and AIDS-related cachexia
Renal cell carcinoma: Kidney cancer is not sensitive to chemotherapy and radiotherapy. Some clinical trials have proved that thalidomide is effective for kidney cancer.
Metastatic colon cancer
Thalidomide is effective in combination with irinotecan and 5-FU, and also alleviates the most common gastrointestinal adverse effects of the latter
Hepatocellular carcinoma
Hepatocellular carcinoma is a vascular-rich cancer, and thalidomide (inhibition of endothelial cell proliferation and migration) has been reported abroad to be mostly used to treat patients in the progressive stage.
Prostate cancer
Figg et al. randomized controlled trial of the efficacy of Tysodi alone and Tysodi in combination with thalidomide in treating such patients resulted in a 50% decrease in PSA in 35% of the group alone and 53% in the combination group. There was a statistically significant difference between the two groups.
Malignant melanoma
The combination of thalidomide and TMZ by Hwu et al. resulted in partial remission (PR) in 10 out of 38 patients, while the other 4 cases were marginally effective.
Dosage.
The dose starts from 100mg/d to the patient’s maximum tolerance is good, according to clinical observation 100mg/d – 500md/d
Thalidomide is used in the treatment of hematological tumors of
Multiple myeloma Myelodysplastic syndrome Myelofibrosis Leukemia (refractory to relapse) Acute myeloid leukemia Chronic granulocytic leukemia Plasma cell leukemia Macroglobulinemia Lymphoma (refractory to relapse) Amyloidosis Chronic graft-versus-host disease
Rationale for thalidomide in the treatment of hematologic disorders
Hematologic neoplasms: presence of vascular proliferation
Preliminary information: MM, CML, AML, MDS, bone fibrillation, lymphoma and other diseases have some efficacy
thalidomide : Thalomid, Celgene May 26 2006 , FDA Multiple myeloma
1. Thalidomide monotherapy for advanced multiple myeloma (MM)
In 1999, Singhal et al. demonstrated for the first time that thalidomide was effective in MM resistant to conventional or high-dose chemotherapy.
2. Thalidomide in combination with dexamethasone and chemotherapy for advanced multiple myeloma (MM)
A number of studies have confirmed the synergistic effect of thalidomide and dexamethasone, with an efficiency of over 41% in combination.
3. Application in primary multiple myeloma
The combination of thalidomide and dexamethasone was reported in 207 patients with primary treatment advanced MM, and the remission rate was 63% after 4 months
IV. Increased dose of chemotherapy, consolidation maintenance therapy after hematopoietic stem cell transplantation
Dose.
Conventional 50 mg to start, increasing 50 mg weekly until 200-300 mg/day, also small dose therapy 100-200 mg/day, all achieved the same efficacy . Clinical treatment doses are individualized, and the final analysis of the IFM01-02 study was presented at the 2006 ASCO Annual Meeting: 100 mg/day can be used to treat relapsed/refractory multiple myeloma.
Summary.
The clinical efficacy of thalidomide in MM, especially refractory or relapsed MM, is definitive, with few side effects relative to high-dose chemotherapy and bone marrow transplantation, and is easy and inexpensive to use without serious toxicities.
Can be used as a single drug, more commonly ==== in combination Can be used in patients with primary treatment, more commonly in== relapsed, refractory patients
Can be used to induce remission, and more importantly for ===== reducing relapse, maintaining remission, and consolidating efficacy
Myelodysplastic syndromes (MDS)
Several clinical trials of monotherapy for MDS have achieved remission rates of 25%-62%, respectively. Trials have shown that Response Stop acts primarily on the red lineage, with some effect on the other two lineages as well.
Myelofibrosis
This includes chronic idiopathic myelofibrosis CIMF and secondary myelofibrosis. Study of fibrosis in relation to cytokines, TNF-a inhibits ECM synthesis and promotes catabolism
Relapsed refractory lymphoma
Hannea et al. combined with Meroval in 16 cases of relapsed refractory condyloma lymphoma, 13 (81%) achieved remission, including 5 CRs, with a median progression-free survival of 20.6 months to complete remission
Thalidomide for rheumatic immune diseases
Systemic lupus erythematosus (especially for discoid or subacute lupus erythematosus) Rheumatoid arthritis Ankylosing spondylitis Leukoarthritis Recurrent oral ulcers Systemic vasculitis Systemic sclerosis Dry syndrome Adult Still’s disease Polymyositis/dermatomyositis (DM) Erythema nodosum Lipofuscinosis
Immune-related diseases treated with Response Stop: Graft-versus-host disease (GvHD) AIDS-related Kaposi’s sarcoma Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)
Anti-inflammatory effects.
1. In vitro and in vivo experiments have demonstrated that this drug can stabilize liver lysosomal membranes in rats and humans, and antagonize inflammatory mediators such as PGF-2 alpha, acetylcholine, histamine, and 5-hydroxytryptamine.
2.Inhibit the production of inflammatory cytokines (IL-1, 6, TNF-)
Stimulate the production of anti-inflammatory cytokines (IL-4, IL-10)
—– response stop can reduce the phagocytic function of leukocytes by inhibiting the above cytokine effects. It inhibits the chemotaxis of leukocytes to the site of inflammation, thus achieving anti-inflammatory effects.
Application in lupus erythematosus
In 1975, Barba Rubio et al. first reported the significant efficacy of Response Stop in discoid lupus erythematosus. This drug has similar efficacy in subacute cutaneous lupus erythematosus. It is particularly indicated in severe cases where topical corticosteroids and oral chloroquine have failed.
Rheumatoid arthritis (RA)
There is a positive additive effect between Reactive Stop and MTX in the combination treatment of RA.
Wdnsbrough reported that the combination of Response Stop and MTX for RA was effective in improving swelling and tenderness in affected joints at a dose of 50-100 mg/d. If effective, the dose was reduced to 50 mg/d for 6 months, with results usually seen within 1 or 2 months.
Application in ankylosing spondylitis
Huang Feng et al. treated 30 cases of AS with thalidomide and showed maximum efficacy at 6 months.
Leukoarthrosis
Mascaro (1979) first reported that treatment of 18 cases of severe recurrent ulcers in leukoaraiosis with reactive stop was effective, especially in refractory patients. This drug is effective for almost all kinds of recurrent oral ulcers, and its dosage is 100-300mg/d. To prevent recurrence, 25–50/d can be used to maintain treatment for a period of time, and after recurrence, thalidomide is effective and the dosage is reduced.
Recurrent oral ulcerative
Reaction to stop the cure and significant improvement rate of up to 75-100%. Usually the damage disappears within a week in light cases and heals within 1 month in severe cases. Reaction stop can not only control the disease quickly, but also control the recurrence.
Dose: 50 – 100 mg/day for light type; 100 – 300 mg/day for 1-3 months for severe type to start.
Dermatomyositis (DM)
Thalidomide is more effective especially in dermatomyositis with limited lesions, improving clinical symptoms. Dosage 100—200 mg/d.
Erythema nodosum
Patients who have failed to respond to glucocorticosteroid treatment can be treated with this drug, and there are clinical reports of better results.
Thalidomide is used in the treatment of dermatological diseases and related diseases
1.Erythema nodosum leprosum
2.Chronic photosensitivity disorders.
3.Light itchy rash
4.Polymorphic heliotrope
5.Lipitis of light
6.Nodular itchy rash
7. Leukoplakia (Beheet) disease, ulcer)
9?Lupus erythematosus 10.Pruritus
11. Lichen planus (OLP)
12.Jessner-Kanof skin lymphocytic infiltration
13.Langerhans cell histiocytosis
14.Erythrodermic psoriasis
15.Crohn`s disease
16.Nodular disease
17.Dermatomyositis
18.Treatment of nodular lipofuscinosis, lupus lipofuscinosis
19.Negative pyoderma
20.Erythema multiforme
21.Other: atopic dermatitis, solar urticaria, aspergillosis, staining dry skin disease, seed pox-like blister disease
Adverse reactions]
1, toxic effects: this drug is a strong teratogenic drugs, so pregnant women are prohibited, women of childbearing age need to take effective contraceptive measures before application. Pregnancy can only be achieved after 6 months of discontinuation of the drug. Generally occur in the first three months of pregnancy, especially the 45th to 55th day. However, malformations do not always occur during drug administration. No bone marrow suppression, no hepatic, renal, cardiopulmonary, or cerebral toxicity has been reported. Half-death doses have not been measured so far and do not cause chronic toxicity.
This drug does not affect the reproductive organs of those taking it, but acts directly on the embryo at the sensitive stage through the placenta and can be teratogenic at small doses. Therefore, it is contraindicated in women of childbearing age.
Long-term use of large doses of this drug (40g or more) may cause polyneuritis and sensory abnormalities. Once the drug should be discontinued, about 25% completely recovered, 25% improved or partially recovered, and 50% still do not recover after 4 to 5 years of discontinuation.
2, other adverse reactions: common sedative effects, drowsiness, drowsiness, dizziness, headache, constipation, dry mouth, rash, dry skin, edema of the extremities; hyperphagia, nausea, deep vein thrombosis, hypotension, slow heart rhythm (<60 times / min) and other rare. Most of them are mild and tolerable, and can subside after stopping the drug.