[Study on the efficacy and safety of high dose thymopentin combined with trans-artery chemoembolization for primary liver cancer].

OBJECTIVE: To evaluate the efficacy and safety of high doses of thymopentin (10 mg/d) combined with transartery chemoembolization for primary liver cancer. METHODS: Fifty primary liver cancer patients were randomly divided into two groups: therapeutic and control group, and all were treated with transfemoral artery chemoembolization (TACE) with oxaliplatin 150 mg, pharmorubicin 50 mg, 5-Fu 750 mg, CF 300 mg and lipiodol 20 ml. Therapeutic group (25) were added 10 mg thymopentin daily after TACE: i.v. on dl - d5, and im on D6 - D21. RESULTS: There was a significant difference in adverse effect and toxicity such as naupathia,fever, swirl, asthenia observed between two groups (P < 0.05). No difference in either pre- or post-chemotherapy peripheral blood examination and biochemical assay was found between two groups (P > 0.05). In control group, CD4+ cell was 37.92% +/- 8.71% in pre-treatment, which decreased to 29.16% +/- 8.21% in post-treatment with a significant difference (P < 0.01), whereas there was no evident difference in CD4+ cell between pre-treatment and post-treatment in the treatment group. CONCLUSION: Transartery chemoembolization combined with high dose of thymopentin in the treatment for primary liver cancer is effective and safe, and can significantly improve the immune function and the chemotherapy tolerance.

Tolerability of treatments for viral hepatitis.

Interferon-alpha is the most widely used antiviral drug in chronic hepatitis B and C. Tolerability is usually good and serious adverse effects are rare. Most of the adverse effects are mild or transient and do not necessitate drug withdrawal. More than 90% of patients who are given interferon-alpha achieve 6 months to 1 year of treatment without serious adverse effects. The serious adverse effects usually occur in predisposed patients with pre-existing organ dysfunction. Nevertheless, careful selection of patients for therapy and observation during therapy are recommended. Nucleoside analogues are promising drugs in the treatment of chronic hepatitis B through inhibition of viral DNA polymerase. Lamivudine has been licensed for use in this indication. Its tolerability is excellent even when used for periods of 1 year or more. The main concern is the relatively high incidence of viral resistance resulting in breakthrough during or relapse after therapy. In the treatment of chronic hepatitis C, ribavirin, in combination with interferon-alpha is currently the reference therapy. The main adverse effect is haemolytic anaemia, which necessitates careful monitoring and adjustment of dosage in many cases. Recently, large trials showed the better efficacy of pegylated interferons as compared with standard interferon. The combination of pegylated interferon with ribavirin is under evaluation.

Evaluation of clinical efficacy and tolerability of intravenous high dose thymopentin in advanced melanoma patients.

Thymopentin (TP5) has been recently evaluated as an immunotherapeutic agent for the treatment of cancer. Melanoma is a highly immunogenic malignancy, and in our previous studies the treatment of metastatic melanoma with TP5 showed encouraging results. In the present study, we evaluated the clinical efficacy and tolerability of high dose intravenous TP5 in 16 patients with melanoma which had metastasized to cutaneous and subcutaneous tissue. All patients were given 1 g intravenous TP5 every second day for 7 weeks and were then evaluated; responders were given a subsequent course of 2 g intravenous TP5 every second day for 5 weeks. Six patients showed a partial response after the first course and were given the second course: one patient achieved a complete response, while the other five remained in partial response at the end of the treatment. The mean duration of response was 7.5 months. No drug side effects were observed. Histopathological and immunohistochemical evaluation of regressing metastatic nodules showed the presence of tumour-infiltrating lymphocytes, necrosis, sclerosis, intratumoral vascular proliferation and microthrombosis. Immunophenotyping of lymphoid infiltrates demonstrated the prevalence of CD4+ and CD45RO+ T-lymphocytes in one patient. We conclude that high dose intravenous TP5 three times a week may induce a clinical response in patients with cutaneous and subcutaneous metastases of melanoma without relevant side effects.

Biological activity and clinical efficacy of intravenous high-dose thymopentin in metastatic melanoma patients.

Eight patients with cutaneous metastatic melanoma were submitted to high-dose intravenous thymopentin (TP5) treatment for 5 weeks: three patients received 1 g three times a week, three received 1 g daily and two received 2 g daily. Four out of eight patients presented a partial response of cutaneous lesions lasting for 1-7 months, and six remain alive with evidence of disease after a follow-up of 2-7 months. A remarkable histologic observation is the presence of tumour necrosis, which was seen as both single cells and large confluent areas. The majority of lymphoid cells present in the tumour are CD45RO+ and CD4+. The CD4+ cells might play an important role in the anti-tumour immune local response by secreting cytokines and inducing apoptotic and necrotic cell death. This hypothesis seems to be confirmed by the presence of a high number of CD4+ cells around intratumoral vessels, while the presence of endovascular micro-thrombosis provides indirect evidence of cytokine activity. Cellular lysis may be produced by the activity of both CD8+ and CD4+ lymphoid cells. The role of TP5 may be an activation of CD4+ and CD8+ lymphoid cells. Clinical and pathological data indicate that TP5 is able to produce consistent clinical and immunological effects in melanoma patients with cutaneous metastases.

Safety and efficacy of thymopentin in zidovudine (AZT)-treated asymptomatic HIV-infected subjects with 200-500 CD4 cells/mm3: a double-blind placebo-controlled trial.

Thymopentin, 50 mg subcutaneously (s.c.) 3 times per week, was evaluated in a double-blind, randomized, placebo-controlled trial of zidovudine (AZT)-treated asymptomatic human immunodeficiency virus (HIV)-infected subjects with 200-500 CD4 cells/mm3 at entry. The 352 subjects were prestratified by prior AZT use into stratum I (235 subjects, > 6 months AZT at entry) and stratum II (117 subjects, < or = 6 months AZT at entry). Clinical end points, CD4 cell counts, serum p24, serum immune complex dissociated (ICD) p24, and safety variables were evaluated through 48 weeks, using an intent-to-treat analysis. The two strata were analyzed individually because they yielded different clinical outcomes, with a statistically significant treatment-by-stratum interaction. In stratum I (mean, 16 months AZT at entry) two AIDS or death events occurred in thymopentin and 10 in placebo recipients (p = 0.024; relative risk (RR) estimate, 4.9 [95% confidence limit (CI), 1.1 to 22.2]). There were three AIDS-related complex (ARC), AIDS, or death events in thymopentin and 18 in placebo recipients [p = 0.001; RR estimate, 5.9 (95% CI, 1.7 to 20.0)]. In stratum II (mean, 3 months AZT at entry), four AIDS or death events occurred in thymopentin and none in placebo recipients (p = 0.11), and four ARC, AIDS, or death events occurred in thymopentin and two in placebo recipients (p = 0.79). The treatment groups did not differ significantly with respect to changes in CD4 counts or p24 antigen levels or with respect to clinical adverse experiences or laboratory abnormalities. Thus, AZT-experienced placebo-treated subjects had relatively high progression rates to AIDS or death and to ARC, AIDS, or death, and these rates were reduced by thymopentin treatment. In contrast, placebo-treated subjects with little prior AZT experience had low progression rates; these were not significantly changed by thymopentin treatment. There was no increase in the incidence of adverse reactions with thymopentin.

A randomized controlled trial of thymopentin therapy in patients with chronic hepatitis B.

Strategies of treatment of chronic hepatitis type B are currently based on the use of either antiviral or immunomodulatory agents. A randomized, controlled trial was performed to assess the safety and efficacy of 6-month thymopentin therapy in 30 patients with chronic hepatitis B. Inclusion criteria were biopsy-proven chronic hepatitis, elevated alanine aminotransferase and serum HBsAg and HBV-DNA positivity for at least 12 months. At the conclusion of the study (1 year), HBV-DNA was negative and alanine aminotransferase had normalized in 13% and 20% of treated cases and in 20% and 27% of controls. None of the ten treated and one of the nine control patients who were initially HBeAg positive subsequently cleared HBeAg. None became HBsAg negative. A histologic improvement was noted in 27% of the treated patients compared with 18% of controls. These results indicate that this regimen of thymopentin therapy is not effective in treating chronic hepatitis B.

A prospective randomized trial of thymopentin versus granulocyte--colony stimulating factor with or without thymopentin in the prevention of febrile episodes in cancer patients undergoing highly cytotoxic chemotherapy.

One hundred patients with advanced carcinoma undergoing highly cytotoxic chemotherapy were enrolled in a prospective randomized trial comparing subcutaneous G-CSF, thymopentin, a combination of the two, and placebo as preventive treatment of febrile leukopenia. Data from this study show that G-CSF was very active in reducing the incidence of chemotherapy-related fever and leukopenia as compared to placebo (22% versus 64%). This difference was statistically highly significant (P < 0.001). Thymopentin was associated with a reduction in febrile episodes as compared to placebo (52% versus 64%), but this difference did not reach statistical significance. Moreover, the addition of thymopentin to G-CSF did not result in a statistically significant improvement of results obtained with G-CSF alone. Similar results were achieved for fungal infections. Tolerance to thymopentin was excellent, while less than 9% of patients on G-CSF treatment complained of mild nausea and generalized bone pain.

Maintenance of CD4+ cells by thymopentin in asymptomatic HIV-infected subjects: results of a double-blind, placebo-controlled study.

OBJECTIVE: To assess the efficacy and safety of thymopentin in HIV-infected patients who had not yet developed AIDS. DESIGN: Patients were stratified into asymptomatic or symptomatic groups and randomized to receive either thymopentin (50 mg) or placebo, subcutaneously, double-blind for 24 or 52 weeks, three times a week. SETTING: Patients were enrolled at three sites (two hospital clinics and one private practice). PATIENTS: Of 91 HIV-seropositive patients (52 asymptomatic and 39 symptomatic) from whom HIV could be isolated from peripheral blood, 45 were enrolled for 24 weeks and 46 for 52 weeks of double-blind evaluation. MAIN OUTCOME MEASURES: Virological, immunological and clinical evaluations were performed before and during treatment. RESULTS: Thymopentin-treated asymptomatic patients had more CD4+ cells, as demonstrated by a greater area under the percentage CD4+ cells curve (P = 0.03) and a shorter median time to a 20% increase in percentage of CD4+ cells (P = 0.04) in the first 24 weeks, with similar trends in the 52-week study. By 24 weeks no asymptomatic thymopentin-treated and two placebo-treated patients (9.1%, Kaplan-Meier estimate) had progressed to constitutional symptoms (P = 0.12; two-tailed Wilcoxon-Gehan test), with only one further progression in a placebo-treated patient in the subset followed for 52 weeks. Symptomatic patients receiving thymopentin or placebo were similar in both CD4+ cell levels and disease progression (two progressions to AIDS in each group). No serious adverse effects attributable to thymopentin were observed. CONCLUSIONS: These results, if confirmed, indicate that thymopentin, by maintaining CD4+ cells, could slow or arrest immune decline and consequent disease progression at the asymptomatic stage of HIV infection.