Thymic peptides for treatment of cancer patients.

BACKGROUND: Purified thymus extracts (pTE) and synthetic thymic peptides (sTP) are thought to enhance the immune system of cancer patients in order to fight the growth of tumour cells and to resist infections due to immunosuppression induced by the disease and antineoplastic therapy. OBJECTIVES: To evaluate the effectiveness of pTE and sTP for the management of cancer. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2010, Issue 3), MEDLINE, EMBASE, AMED, BIOETHICSLINE, BIOSIS, CATLINE, CISCOM, HEALTHSTAR, HTA, SOMED and LILACS (to February 2010). SELECTION CRITERIA: Randomised trials of pTE or sTP in addition to chemotherapy or radiotherapy, or both, compared to the same regimen with placebo or no additional treatment in adult cancer patients. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from published trials. We derived odds ratios (OR) from overall survival (OS) and disease-free survival (DFS) rates, tumour response (TR) rates, and rates of adverse effects (AE) related to antineoplastic treatments. We used a random-effects model for meta-analysis. MAIN RESULTS: We identified 26 trials (2736 patients). Twenty trials investigated pTE (thymostimulin or thymosin fraction 5) and six trials investigated sTP (thymopentin or thymosin α(1)). Twenty-one trials reported results for OS, six for DFS, 14 for TR, nine for AE and 10  for safety of pTE and sTP. Addition of pTE conferred no benefit on OS (RR 1.00, 95% CI 0.79 to 1.25); DFS (RR 0.97, 95% CI 0.82 to 1.16); or TR (RR 1.07, 95% CI 0.92 to 1.25). Heterogeneity was moderate to high for all these outcomes. For thymosin α(1) the pooled RR for OS was 1.21 (95% CI 0.94 to 1.56, P = 0.14), with low heterogeneity; and 3.37 (95% CI 0.66 to 17.30, P = 0.15) for DFS, with moderate heterogeneity. The pTE reduced the risk of severe infectious complications (RR 0.54, 95% CI 0.38 to 0.78, P = 0.0008; I² = 0%). The RR for severe neutropenia in patients treated with thymostimulin was 0.55 (95% CI 0.25 to 1.23,  P = 0.15). Tolerability of pTE and sTP was good. Most of the trials had at least a moderate risk of bias. AUTHORS' CONCLUSIONS: Overall, we found neither evidence that the addition of pTE to antineoplastic treatment reduced the risk of death or disease progression nor that it improved the rate of tumour responses to antineoplastic treatment. For thymosin α(1), there was a trend for a reduced risk of dying and of improved DFS. There was preliminary evidence that pTE lowered the risk of severe infectious complications in patients undergoing chemotherapy or radiotherapy.

[Use of tactivin and imunofan for the treatment of patients with endometrial carcinoma]. / Primenenie taktivina i immunofana pri lechenii bol'nykh adenokartsinomoi éndometriia.

Immunofan and tactivin, employed as a means of immunological correction in the complex treatment of adenocarcinoma, decrease the onset frequency of radiation-induced complications and exhibit a pronounced immunocorrector effect. This was indicated by increasing level of lymphocytes (including CD3+, CD4+, CD8+, and CD19+), helper coefficient (CD4+/CD8+), and phagocyte activity of neutrophils, as well as by the tendency to normalization of the HCT-test results. Immunofan somewhat exceeds tactivin in the efficacy of endometrium adenocarcinoma treatment.

[Immunomodulating therapy of psoriasis vulgaris]. / Immunmodulierende Therapie bei Psoriasis vulgaris.

BACKGROUND: Newest studies have shown that psoriasis is not primarily a skin disorder but an immunological disturbance under the skin. The skin manifestations are a result of overstimulation of superficial skin cells (Langerhans cells) due to increased production of interleukin 2, 6 and 8 as well as transforming growth-factor-alpha. Interleucin-10 production is diminished. In a recent study (11 German University Skin Clinics) fumaric acid was shown to improve the skin leasons in 80% of treated patients. OWN EXPERIENCES: Our own studies on 54 patients which where treated in addition with intravenous thymus extract (Thymoject) and selenium (Selenase) showed a faster healing rate with fumaric acid alone. From these results one can postulate that the above treatments (fumaric acid, thymus and selenium) have a synergystic effect. CONCLUSIONS: Internal immunmodulating treatments should therefore have preference over external symptomatic treatments like UV-light, ointments, salt water bath, etc.

[Combined immunomodulating therapy in rheumatoid arthritis]. / Kombinirovannaia immunomoduliruiushchaia terapiia revmatoidnogo artrita.

Monotherapy with methotrexate (MT) was compared to combined therapy MT+tactivin (T) in a 2-year clinical trial including 127 patients with rheumatoid arthritis (RA). MT was given to 88 patients in a weekly dose 7.5 mg. In 39 patients this dose was given in combination with subcutaneous injections of T (100 micrograms two times a week for a months, then once a week). Both treatments induced a significant decline in severity of arthralgia, in the number of joints with inflammation, in the level of C-reactive protein and in ESR. Morning stiffness and pains in the joints at palpation were achieved after MT+T combination. Side effects were similar in both treatments.

Interferon and thymic hormones in the therapy of human myocarditis and idiopathic dilated cardiomyopathy.

It is becoming increasingly apparent that idiopathic dilated cardiomyopathy (IDC) probably results from an acute viral myocarditis. One reasonable hypothesis is that persistent viral infection causes myocardial destruction leading to left ventricular dilatation and heart failure. The aim of this study was to evaluate the efficacy of interferon-alpha (IFN) and thymomodulin in the treatment of idiopathic myocarditis and IDC. Clinical, immunological, haemodynamic and histological evaluation was performed in 40 patients before inclusion in the study. Patients were randomized into three treatment groups: (a) conventional therapy plus IFN, (b) conventional therapy plus thymomodulin and (c) conventional therapy alone. Two-year follow-up included repeated endomyocardial biopsy, echocardiographic evaluation, treadmill exercise test, Holter monitoring study and radionuclide assessment of left ventricular function during exercise. Left ventricular ejection fraction increased during follow-up in most of the IFN-and thymomodulin-treated patients, and only in a few of conventionally treated patients. Left ventricular reserve was significantly higher at 2-year follow-up in patients treated with immunomodulators. No serious adverse effects were noticed during treatment. Our results suggest that treatment of myocarditis and/or IDC with IFN or thymomodulin induces an earlier and significantly superior clinical improvement than conventional therapy alone.

High-dose folinic acid (FA) and fluorouracil (FU) plus or minus thymostimulin (TS) for treatment of metastatic colorectal cancer: results of a randomized multicenter clinical trial.

The purpose of this study was to ascertain the possible protective effect of thymostimulin (TS) on chemotherapy-induced leukopenia and related febrile episodes, beside the potential of improving therapeutic efficacy and tolerability of high-dose folinic acid (FA) plus fluorouracil (FU) in metastatic colorectal cancer. In 211 evaluable patients the objective responses were 19/105 (18%) in the FA-FU arm versus 32/106 (30%) obtained with the same regimen plus TS. The difference was statistically significant (p = 0.02). No difference was observed in terms of hematological toxicity, while the TS treated patients experienced a significantly lower incidence of mucositis and diarrhoea (p = 0.03). No significant differences were recorded in the incidence of febrile episodes and other treatment-related toxicities. The possibility of improving response to chemotherapy in advanced colorectal cancer without increasing systemic toxicity is particularly interesting and deserves further attention.

Combined systemic beta-interferon and thymostimulin administration for metastatic brain tumors. A brief report.

Interferon-beta (IFN-B) plus thymostimulin (Th) were administered for eight weeks, intravenously and by intramuscular route to eight patients with metastatic brain tumors. No patient had a complete response. One had a stable disease and seven a progressive disease during that time. The mechanisms of the action of IFN-B and Th, and the possible therapeutic value are discussed.

Nonspecific immunostimulation with low doses of cyclophosphamide (LDCY), thymostimulin, and Echinacea purpurea extracts (echinacin) in patients with far advanced colorectal cancers: preliminary results.

Outpatients (n = 15) with metastasizing far advanced colorectal cancers received immunotherapy consisting of low-dose cyclophosphamide (LDCY) 300 mg/m2 every 28 days i.v., thymostimulin 30 mg/m2, days 3-10 after low-dose cyclophosphamide i.m. once daily, then twice a week, and echinacin 60 mg/m2 together with thymostimulin i.m. All patients had had previous surgery and/or chemotherapy and had progressive disease upon entering the study. Two months after onset of therapy a partial tumor regression was documented in one and a stable disease in 6 other patients by abdominal ultrasonography, decrease of the tumor markers carcinoembryonic antigen (CEA), CA 19-9, CA 15-3, and/or chest roentgenography, which may also be attributed to the natural course of disease. Mean survival time was 4 months, 2 patients survived for more than 8 months. Immunotherapy was well tolerated by all patients without side effects.

Severe anaphylactic reaction to thymostimulin.

Thymostimulin is a partially purified extract of calf thymus, consisting of a group of polypeptides with a total molecular weight of approximately 12,000 D. It is used as an immunologic response modifier in primary and secondary immunodeficiencies. We report a patient who had a severe anaphylactic reaction with the first injection of thymostimulin. Type I hypersensitivity to thymostimulin was suggested by an immediate skin test response, specific IgE determination by indirect ELISA and a positive histamine release test. This patient also reacted to bovine serum albumin (BSA), fetal calf serum (FCS) and cow hair and dander. The controls did not react to any of these tests. Clinicians need to be aware that the use of medical products of xenogeneic origin may lead to severe allergic reactions.

A double-blind, placebo-controlled trial of thymostimulin in symptomatic HIV-infected patients.

The potential therapeutic efficacy of the thymic hormone preparation, thymostimulin (TP1), in HIV infection has been studied in a multi-institutional, randomized, double-blind, placebo-controlled trial. Fifty evaluable patients with advanced AIDS-related complex (ARC) were injected with TP1 or placebo twice weekly for 6 months after 2 weeks of daily injections. The primary endpoint, progression to AIDS, was reached in nine TP1- and 11 placebo-treated subjects after 1 year. CD4 cell numbers were not affected by administration of the study drug. No toxicity was associated with TP1 treatment. We conclude that TP1 is ineffective in altering the progress of HIV disease in patients with advanced ARC.

[Immunocorrective therapy of pyelonephritis in children]. / Immunokorrigiruiushchaia terapiia pielonefrita u detei.

A total of 40 children who suffered from acute or chronic pyelonephritis underwent immunological treatment with polypeptide drug tactivin. There was an evidence of clinical and laboratory improvement in 82.5 per cent of treated persons, first manifest in decreased proteinuria and normalized urinary sedimentation, and then in lower levels of bacteriuria due to the developing resistance to infectious agents. In 15 per cent of tactivin-treated children leukocyturia persisted though the disease progression was hindered. In the course of the treatment no side-effects were noted. In line with the stimulation of humoral immune response and activation of the complement system, tactivin administration evoked the competence of T-lymphocytes and potentiated the development of this link of immune system. As part of combined treatment the above preparation favourably affected the disease pathogenesis in children.

Phase I/II trial of thymostimulin in opportunistic infections of the acquired immune deficiency syndrome.

Fifteen patients with acquired immune deficiency syndrome (AIDS) and opportunistic infection, were randomized to receive treatment with either thymostimulin (TP-1) at 1 mg/kg for 14 days then weekly for 12 weeks or placebo. The objectives of this study were to evaluate the toxicity of TP-1 in this patient population and to make observations on clinical response as measured by time to second opportunistic infection (OI) and changes in laboratory parameters of immune function. The study demonstrates that TP-1 can be administered safely. There were no differences, however, in time to second OI or overall survival between patient groups. In addition, no change in the immune function could be detected in patients receiving thymostimulin.

Thymostimulin in the treatment of hepatitis B surface antigen-positive chronic active hepatitis. Controlled clinical trial--two years follow-up.

In this paper results obtained with thymostimulin (TP-1 Serono) in patients with hepatitis B surface antigen (HBsAg)-positive chronic active hepatitis after 2 years follow-up are reported. The favourable trend observed in a previous trial was confirmed after a longer observation period, most patients showing a significant amelioration of clinical, biochemical and histological parameters, with respect to control group. Hepatitis B virus (HBV) serology, too, showed a significantly higher rate of seroconversion and antigen disappearance in treated patients. Finally, hospitalization period of the latter was significantly lower. These results, though obtained in a small population of patients, seem to indicate a role for thymic hormone therapy in the management of chronic active hepatitis.

[Ultrastructure of the blood lymphoid cells and the dynamics of cellular immunity indices in chronic lympholeukemia patients during immunocorrection with T-activin]. / Ul'trastruktura limfoidnykh kletok krovi i dinamika pokazatelei dletochnogo immuniteta u bol'nykh khronicheskim limfoleikozom v protsesse immunokorrektsii T-aktivinom.

Fourteen patients with chronic lymphoid leukemia who received treatment with T-activin given in courses (800-1100 micrograms) were examined for ultrastructure of blood lymphoid cells and the time-course of changes in humoral immunity. The patients had not received chemotherapy or hormonal treatment before. During the treatment with T-activin, no chemotherapeutic remedies were administered. After immunocorrection chemotherapy and hormones were prescribed when necessary. In the patients, the number of E-RFC (T cells) rose, whereas the number of B cells carrying surface immunoglobulins and the number of Em-RFC decreased. At the same time the prolonged use of T-activin brought about an increase in the number of B cells containing heavy chains of immunoglobulins M, G and A in the cytoplasm, while no considerable rise of serum immunoglobulins M, G and A was detected. Ultrastructural studies made during the use T-activin demonstrated a double rise in the number of lymphoplasmocytes, and in that of wide-plasma lymphocytes. The latter ones measuring 10 to 12 microns showed hypertrophy of Golgi's complexes and of the endoplasmic network. It is suggested that administration of T-activin for the B cell version of chronic lympholeukemia produces the differentiation of B cells, accompanied by the appearance in the cytoplasm of heavy chains of immunoglobulins M, G and A, which is supported by immunological and morphological analysis.

[Improved immunocompetence in two children with chronic Epstein-Barr virus infection under treatment with a standardized thymus hormone preparation (thymostimulin)]. / Verbesserte Immunkompetenz bei zwei Kindern mit chronischer Epstein-Barr-Virusinfektion unter der Behandlung mit einem standardisierten Thymushormon-Präparat (Thymostimulin).

Two children with chronic Epstein-Barr virus infection were treated with a standardized thymic hormone preparation (thymostimulin, TP-1 Serono). The treatment was well tolerated. No adverse reactions, no side effects were observed. Results of immunological investigations showed a trend towards normalisation. Additional clinical evidence showed up, which pointed to a response to the therapy.

A placebo-controlled trial of thymic hormone treatment of recurrent herpes simplex labialis infection in immunodeficient host: results after a 1-year follow-up.

Twenty-one immunodeficient patients with recurrent herpes simplex labialis (HSL) were randomly allocated to either the saline or the bovine thymus extract Thymostimulin (TS) group and treated for a period of 6 months. A total of 17 recurrences with a mean severity index of 266.2 +/- 192 in the TS-treated group versus a total of 62 recurrences in the placebo group (score 458.8 +/- 299.6) were observed after 12 months of follow-up. A significant increase of total WBC (P less than 0.05 versus control group), lymphocyte count, and T-cell number (P less than 0.001) were detected in the TS group after 6 months as well as after 12 months. In vitro lymphoproliferative responses to herpes simplex virus antigen and natural killer cell activity were also significantly higher (P less than 0.05) in the TS group, whereas no significant difference in antibody titers to herpes simplex could be detected between the two groups. TS may be potentially useful in preventing viral reactivation in immunocompromised hosts by potentiating cell-mediated immune responses. Further studies evaluating TS for prophylaxis of infection in patients at risk should be considered.