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Life Extension Magazine

LE Magazine July 2001

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Page 2 of 3

HIV

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Stimulation of the immune system, especially in combination with antiviral agents, has received considerable interest as a potential means to treat acquired immune deficiency syndrome (AIDS) and HIV-infected patients

Stimulation of the immune system, especially in combination with antiviral agents, has received considerable interest as a potential means to treat acquired immune deficiency syndrome (AIDS) and HIV-infected patients. Studies have shown a high degree of immune restoration from the combined administration of thymosin alpha-1 and alpha inteferon (IFNa). Thymosin alpha-1 in combination with AZT and IFNa has been investigated for treatment of HIV-infected patients.

At the University of Rome, a group of researchers conducted a study to investigate the combination of thymosin alpha-1, IFNa and AZT for treatment of HIV-infected patients with CD4 counts of 500 or lower.(21) The study included seven patients in each of four treatment groups: thymosin alpha-1 plus IFNa plus AZT; thymosin alpha-1 plus AZT; IFNa plus AZT; and AZT.

Treatment was continued for 12 months for the majority of patients, with up to 18 months for a smaller cohort of patients. After one year, the thymosin alpha-1 plus IFNa plus AZT combination therapy resulted in a statistically significant increase in CD4 cells and stimulation of lymphocyte cytotoxic activity against natural killer-sensitive target cells compared with the other three treatment groups.

Vaccines

Immune senescence, considered an aging process, has been related to a gradual decline in thymus function and thymic hormone production. The lack of thymic hormones may contribute to the decline in immune function, particularly the T cell component.(22-24) In the elderly, antibody response after vaccination is compromised when compared to response in young.(25,26) This may be one factor that accounts for insufficient efficacy of certain vaccination programs (e.g., influenza).

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In the elderly,antibody response after vaccination is compromised when compared to response in young. This may be one factor that accounts for insufficient efficacy of certain vaccination programs (eg., influenza)

A similar diminished antibody response has been reported in patients with end-stage renal disease (ESRD) and in hemodialysis patients. In hemodialysis patients, this has been attributed to incompetence in T cell-mediated immune responses.(27-31) Since thymosin alpha-1 can enhance T-cell-dependent specific antibody production, the addition of thymosin alpha-1 to vaccination programs for immunocompromised individuals should be effective.

Six clinical studies have been completed that evaluated the efficacy of thymosin alpha-1 as an adjuvant for influenza and hepatitis B antiviral vaccines in subjects immunocompromised due to age or hemodialysis. When compared to vaccine plus placebo, administration of thymosin alpha-1 in conjunction with vaccine increased and sustained the specific antibody response, increased protection against illness, and overcame previous lack of specific antibody response and age-associated decline in specific antibody response. No serious adverse effects were observed in any of the studies.

Cancer

The therapeutic usefulness of thymosin alpha-1 has been examined in several types of cancers. The rationale for such use is that thymosin alpha-1 has efficacy in several animal cancer models and has been shown to improve immune function. Patients with some cancers have depressed cellular immunity, and progression of some cancers appears to be related to impaired suppression of the tumors by the immune system. This has been shown to be the case for hepatocellular carcinoma, non-small-cell lung cancer and melanoma.

Thymosin alpha-1 dosing regimen

The dosing regimen for thymosin alpha-1 varies with the disease it is treating.

In one study of hepatitis B, 1.6 mg of thymosin alpha-1 was administered twice weekly for six months.(1) Because its effectiveness can be increased by using it combination with other drugs, this dosage can be augmented with twice-weekly three MIU injections of low-dose lymphoblastoid interferon
.(2)

In clinical studies, the dosage levels for hepatitis C were similar.(3)

In cancer studies, thymosin alpha-1 was often combined with several other drugs in a complex treatment regimen that might have included chemotherapy, interleukin-2 or interferon. Thymosin alpha-1 has shown efficacy against certain kinds of cancers, including hepatocellular carcinoma (HCC), non-small cell-lung-cancer and malignant melanoma.

In one study for hepatocellular carcinoma, patients were treated with .9 micrograms per square meter for six months, in conjunction with transcatheter arterial chemoem-bolization mixed with 40 mg to 60 mg of doxorubicin.
(4)

In a monotherapy study for non-small-cell-lung-cancer, patients recieved .9 micrograms per square meter biweekly thymosin alpha-1 for one year after radiation treatment.(5)

In another study on lung cancer, thymosin alpha-1 was administered at a dosage of 1 mg/day on days 8 to 11 and 15 to 18 after chemotherapy. The thymosin alpha-1 cycles were alternated with interferon alpha-2a.(6)

As part of a multimodal treatment approach for malignant melanoma, thymosin was given after chemotherapy in a dose of 2 mg on days 4 to 7. On day 8, interleukin-2 was given until day 12. This cycle (chemotherapy/thymosin alpha-1/interleukin) was repeated every three weeks.(7)

In a study for HIV, patients were given a combination of AZT (500 mg/day), interferon (2 MIU BIW) and thymosin alpha-1 (1.0 mg BIW).(8)


1. Chien RN, Liaw YF, Chen TC, Yeh CT, Sheen IS. Efficacy of thymosin alpha-1 in patients with chronic hepatitis B: a randomized, controlled trial. Hepatology 1998; 27:1383-7.

2. Rasi G, Mutchnick MG, Di Virgilio D, et al. Combination low-dose lymphoblastoid interferon and thymosin alpha-1 therapy in the treatment of chronic hepatitis B. Journal of Viral Hepatitis 1996; 3: 191-196.

3. Sherman KE, Sjogren M, Creager RL, et al. Combination therapy with thymosin alpha-1 and interferon for the treatment of chronic hepatitis C infection: a randomized, placebo-controlled double-blind trial. Hepatology 1998; 27:1128-35.

4. Stefanini GF, Foschi FG, Castelli E, et al. Alpha-1-thymosin and transcatheter arterial chemoembolization in hepatocellular carcinoma patients: a preliminary experience. Hepatogastroenterology 1998; 45:209-15.

5. Schulof RS, Lloyd MI, Cleary PA, et al. A randomized trial to evaluate the immunorestorative properties of synthetic thymosin alpha-1 in patients with lung cancer. Journal of Biological Response Modifiers 1985; 4:147-158.

6. Lopez M, Di Lauro L, Vici P, et al. Biological agents and chemotherapy in the treatment of solid tumors, Third International Symposium on Combination Therapies, Houston, Texas, 1993. Institute for Advanced Studies in Immunology & Aging.

7. Lopez M, Carpano S, Cavaliere R, DiLauro L, Ameglio F, Vitelli G. Biochemotherapy with thymosin alpha-1, interleukin-2 and dacarbazine in patients with metastatic melanoma: clinical and immunological effects. Annals of Oncology 1994; 5:741-746.

8. Garaci E, Rocchi G, Perroni L, et al. Combined therapy with zidovudine-thymosin alpha-1 alpha interferon in the treatment of HIV-infected patients. Second International Symposium on Combination Therapies, Sicily, Italy, 1992.

Primary liver cancer is the most prevalent malignant disease in the world, killing up to 1.25 million people every year. Hepatocellular carcinoma accounts for more than 80% of all primary liver tumors and has a worldwide annual incidence of approximately one million new cases.(32) Although hepatocellular carcinoma is a common malignancy in Africa and Asia, it accounts for approximately 4,000 to 6,000 cases per year in the United States.(33)

When identified in its early stages, hepatocellular carcinoma can be treated with surgical resection or liver transplantation, and some patients may be cured. However, sometimes the disease is not amenable to surgical treatment, either because of tumor size or because of poor liver function. In these situations the prognosis is dire. Other treatment approaches have been tried when surgery or liver transplantation are not feasible. Chemotherapy results are mixed.

One study involving 12 patients examined thymosin alpha-1 for treatment of primary liver cancer.(34) The patients were treated with thymosin alpha-1 for six months, in addition to transcatheter arterial chemoembolization (TACE) mixed with 40 mg to 60 mg of doxorubicin. Patients treated with the combination of thymosin alpha-1 plus TACE showed longer survival compared to the control group treated with TACE alone.

Thymosin alpha-1 has also been used to treat non-small-cell lung cancer. This cancer accounts for approximately 75% of lung cancer cases, and current therapies such as radiation therapy and chemotherapy give disappointing results.(35,36)

A trial at George Washington University Trial involved 42 patients with lacalized, unresectable non-small cell lung cancer who were treated following radiation therapy for up to one year or until relapse.(37) Patients received either thymosin alpha-1 biweekly or placebo. Thymosin alpha-1 administration resulted in an improvement of T cell levels that had been depleted by radiation therapy and an increase in the percentage of lymphocytes expressing the pre-T cell and helper/inducer T cell surface markers. Both thymosin alpha-1 groups had statistically significant improvements in relapse-free and overall survival.

In a trial conducted in Italy involving 60 subjects, patients with non-small-cell lung cancer were treated with thymosin alpha-1 in combination with chemotherapy (cisplatin and etoposide) and interferon. Of the 55 evaluable patients, there was an overall response rate of 44%. Median survival was 12.6 months.(38)

Another form of cancer, malignant melanoma, is resistant to most forms of therapy. Response rates to dacarbazine (DTIC), the most active single agent, are approximately 17% to 20%, and have no impact on patient survival.(39-41) The effects of thymosin alpha-1 in combination with chemotherapy and cytokine therapy for treatment of malignant melanoma were examined in three trials in Italy with comparisons to historical controls.

In one trial,(42) in 26 treated patients evaluated by World Health Organization (WHO) criteria, there was an overall response rate of 50%. In another trial with the same combination treatment, 20 patients with stage III or IV metastatic melanoma were treated.(43) Ten patients responded to therapy for an overall response rate of 50%. Median survival time was 11.5 months with a median time to progression of 5.5 months. Importantly, 7 patients survived for more than 12 months and 3 patients were disease free after more than 3 years. In the third trial, there were 42 evaluable patients that showed an objective response rate of 36%, with a median time to progression of 5.5 months and median survival of 11 months.

Side Effects

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Thymosin alpha-1 has been shown to be well tolerated even in patients with decompensated liver disease. Because of its excellent safety profile, it may be combined with other therapies to enhance their efficacy without increasing toxicity

In general, thymosin alpha-1 has an excellent history and shows a remarkable lack of side effects. Since 1979, it has been evaluated in more than 3,000 patients in over 70 clinical studies. Administration has been in daily doses ranging from 0.6 mg/m2 to 9.6 mg/m2 and 1 mg to 16 mg for treatment periods ranging from 1 day to 18 months. No serious adverse experiences have been observed. Thymosin alpha-1 has been shown to be well tolerated even in patients with decompensated liver disease, renal disease requiring hemodialysis and primary immunodeficient individuals.

The lack of significant side effects with thymosin alpha-1 is in sharp contrast to other major immune modulators such as interferon and interleukin. The side effects and toxicities of these drugs make them difficult for most patients to tolerate. Interferon creates flu-like side
effects (fever, chills, malaise and headaches), and interleukin causes significant edema in the lungs and elsewhere. Thymosin alpha-1, whether used alone or in conjunction with these drugs, has shown an impressive range of benefits.

References on Page 3 of 3



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