Functional recovery following traumatic brain injury in rats is enhanced by oral supplementation with bovine thymus extract.

Traumatic brain injury (TBI) is one of the leading causes of death worldwide. There are currently no effective treatments for TBI, and trauma survivors suffer from a variety of long-lasting health consequences. With nutritional support recently emerging as a vital step in improving TBI patients' outcomes, we sought to evaluate the potential therapeutic benefits of nutritional supplements derived from bovine thymus gland, which can deliver a variety of nutrients and bioactive molecules. In a rat model of controlled cortical impact (CCI), we determined that animals supplemented with a nuclear fraction of bovine thymus (TNF) display greatly improved performance on beam balance and spatial memory tests following CCI. Using RNA-Seq, we identified an array of signaling pathways that are modulated by TNF supplementation in rat hippocampus, including those involved in the process of autophagy. We further show that bovine thymus-derived extracts contain antigens found in neural tissues and that supplementation of rats with thymus extracts induces production of serum IgG antibodies against neuronal and glial antigens, which may explain the enhanced animal recovery following CCI through possible oral tolerance mechanism. Collectively, our data demonstrate, for the first time, the potency of a nutritional supplement containing nuclear fraction of bovine thymus in enhancing the functional recovery from TBI.

ThymicPeptides Reverse Immune Exhaustion in Patients with Reactivated Human Alphaherpesvirus1 Infections.

Recurrent infection with human alphaherpesvirus 1 (HHV-1) may be associated with immune exhaustion that impairs virus elimination. Thymic peptides enhance immune function and thus could overcome immune exhaustion. In this study, we investigated whether reactivation of herpes infections was associated with immune exhaustion. Moreover, we examined the impact of treatment with thymostimulin on the expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) on T and B lymphocytes in patients suffering from recurrent HHV-1 reactivation. We also assessed the effector function of peripheral blood mononuclear cells (PBMCs) after stimulation with thymic peptides. We enrolled 50 women with reactivated HHV-1 infections and healthy volunteers. We measured the expression of various activation and exhaustion markers on the surface of PBMCs using flow cytometry. In ex vivo experiments, we measured the secretion of inflammatory cytokines by PBMCs cultured with thymostimulin. Compared with controls, patients with reactivated HHV-1 infections had increased percentages of CD3+ co-expressing CD25, an activation marker (p < 0.001). Moreover, these patients had increased percentages of CD4+ and CD8+ cells co-expressing the inhibitory markers PD-1 and PD-L1. In cultures of PBMCs from the patients, thymostimulin increased the secretion of interferon gamma (p < 0.001) and interleukin (IL)-2 (p = 0.023), but not IL-4 or IL-10.Two-month thymostimulin therapy resulted in no reactivation of HHV-1 infection during this period and the reduction of PD-1 and PD-L1 expression on the surface of T and B lymphocytes (p < 0.001). In conclusion, reactivation of herpes infection is associated with immune exhaustion, which could be reversed by treatment with thymic peptides.

[HUMAN CYTOMEGALOVIRUS INFECTION AND SPONTANEOUS ABORTION IN PREGNANT WOMEN OF I AND II TRIMESTER].

The goal of this work was the evaluation of the frequency of human CMV infection among the women, whose pregnancy ended in miscarriage, detection of active forms of infection and treatment before pregnancy. Virological and sero-immunological techniques were used. A total of 116 women who had miscarriages before the 28 week of pregnancy were submitted to the CMV test. 109 women (94.0%) demonstrated positive results. 49 women (42.2%) had active form of the cytomegalovirus infection. 13 women (26.5%) had the recurrent form and 36 patients (73.5%) had the persistent form of CMV infection (stage of productive replication). All the women with active CMVI were treated before the next pregnancy. Immunomodulatory therapy for the treatment was used.

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.

Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma: a phase III clinical trial.

BACKGROUND: Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess the efficacy of thymostimulin in a phase III trial. METHODS: The study was designed as a prospective randomised, placebo-controlled, double-blind, multicenter clinical phase III trial. Between 10/2002 and 03/2005, 135 patients with locally advanced or metastasised HCC (Karnofsky >or=60%/Child-Pugh

[Influence of peptides from pineal gland on thymus function at aging].

The interference between thymus and pineal gland during their involution is considered in this review. The research data about influence of thymus peptides on pineal gland and pineal peptides on thymus is summarized. Analysis of these data showed that pineal peptides (epithalamin, epitalon) had more effective geroprotective effect on thymus involution in comparison with geroprotective effect of thymic peptides (thymalin, thymogen) on involution of pineal gland. The key mechanisms of pineal peptides effect on thymus dystrophy is immunoendocrine cooperation, which is realized as transcription's activation of various proteins.

Trichinella spiralis: Effect of thymus factor X on apoptosis and necrosis in mice.

The aim of the study was to determine the effect of thymus factor X (TFX-Jelfa) on the percentage of apoptotic and necrotic lymphocytes in the spleen, mesenteric lymph nodes, and muscle tissue of mice infected with 200 larvae of Trichinella spiralis. TFX was administered subcutaneously at a dose of 15mg/kg. On days 7, 14, 21, 28, 35, 42, and 60 after infection, apoptotic and necrotic cells were detected by flow cytometry after staining with the Annexin V-Fluos Staining Kit. TFX increased the percentage of apoptotic lymphocytes in the spleen, mesenteric lymph nodes, and muscle tissue of mice infected with T. spiralis. The effect of TFX on the percentage of necrotic lymphocytes was weaker and less clear. Parasite load was lower in infected mice treated with TFX than in the untreated control mice. The effect of TFX on the host immune response and the survival of parasite larvae was therefore probably affected by the extent of inflammatory infiltrates, and not by the percentage of lymphocytes undergoing apoptosis.

Thymostimulin in advanced hepatocellular carcinoma: a phase II trial.

BACKGROUND: Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma in vitro. In a phase II trial, we investigated safety and efficacy including selection criteria for best response in advanced or metastasised hepatocellular carcinoma. METHODS: 44 patients (84 % male, median age 69 years) not suitable or refractory to conventional therapy received thymostimulin 75 mg subcutaneously five times per week for a median of 8.2 months until progression or complete response. 3/44 patients were secondarily accessible to local ablation or chemoembolisation. Primary endpoint was overall survival, secondary endpoint tumor response or progression-free survival. A multivariate Cox's regression model was used to identify variables affecting survival. RESULTS: Median survival was 11.5 months (95% CI 7.9-15.0) with a 1-, 2- and 3-year survival of 50%, 23% and 9%. In the univariate analysis, a low Child-Pugh-score (p = 0.01), a low score in the Okuda- and CLIP-classification (p < 0.001) or a low AFP-level (p < 0.001) were associated with better survival, but not therapy modalities other than thymostimulin (p = 0.1) or signs of an invasive HCC phenotype such as vascular invasion (p = 0.3) and metastases (p = 0.1). The only variables independently related to survival in the Cox's regression model were Okuda stage and presence of liver cirrhosis (p < 0.01) as well as response to thymostimulin (p < 0.05). Of 39/44 patients evaluable for response, two obtained complete responses (one after concomitant radiofrequency ablation), five partial responses (objective response 18%), twenty-four stable disease (tumor control rate 79%) and eight progressed. Median progression-free survival was 6.4 months (95% CI 0.8-12). Grade 1 local reactions following injection were the only side effects. CONCLUSION: Outcome in our study rather depended on liver function and intrahepatic tumor growth (presence of liver cirrhosis and Okuda stage) in addition to response to thymostimulin, while an invasive HCC phenotype had no influence in the multivariate analysis. Thymostimulin could therefore be considered a safe and promising candidate for palliative treatment in a selected target population with advanced hepatocellular carcinoma, in particular as component of a multimodal therapy concept. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29319366.

[Immunocorrection in the treatment of diffuse peritonitis in aged patients].

The results of treatment of 161 patients with diffuse forms of peritonitis with, using of the immunostimulators are analyzed. The algorithm of staged complex immunocorrection for patients with acute pancreatitis, including aged patients, is worked out. The use of it improves the results of treatment and allows decrease the morbidity.

Biological response modifiers.

It is clear that the rate of change in biology is rapidly accelerating. This is most apparent in the BRM area with respect to the development of new cancer therapies. New surgical approaches are being developed, and new forms of delivery for therapeutic radiation are now available. Radiosensitizers are now also being tested. Similarly, new chemotherapeutic agents and new methods of utilizing existing drugs are being developed. However, the use of BRM either alone or in combination with these other modalities is the area of greatest change and can be expected to be a major factor in achieving a greater understanding of cancer biology and a greater therapeutic specificity in the treatment of cancer patients in this decade (2, 65). Given the new technology of the 1980's, this is an exciting time. It is hoped that sufficient resources will be available to support continuing efforts to develop biologicals into effective anticancer agents. The rapidly advancing technologies of computers, cell fusion, and genetic engineering are all interrelated through the underpinnings of molecular biology to offer us unparalleled opportunities in biological research. These opportunities should translate into more effective treatments for cancer in this decade.

Effect of the thymic factor, thymostimulin (TP-1), on the survival rate of tumor-bearing mice.

The effect of treatment with the thymic factor thymostimulin (TP-1) on the survival rate of tumor-bearing mice was studied, using C57BL/6 mice inoculated with 1 x 10(5) Lewis lung carcinoma (3LL) cells. TP-1 given from inoculation day (4 mg/kg, twice weekly) caused a delay in the appearance of primary tumor [14.4 +/- 1.1 (S.E.) days in control; 18.5 +/- 1.4 days in TP-1-treated animals; p less than 0.05], without changing ultimate survival rate. When primary tumor was resected, the incidence of fatal lung metastasis increased as a function of tumor size on resection day. TP-1 given after resection (same dose schedule) significantly increased survival rate as compared to resection only, provided that resected tumor diameter was less than 1.7 mm. The combination of TP-1 and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; single i.p. injection, 50 mg/kg) was effective in either resected or nonresected primary tumor. Without resection, TP-1 with CCNU cured (more than 6 months free of tumor; untreated animals died within 30 to 44 days) 55% of the animals, as compared to 23% cured by CCNU alone (p less than 0.01). With resection animal cure rates were: resection (resected tumor diameter, 0.7 to 1.7 mm) alone, 42% cured; resection with CCNU, 47% cured; resection with TP-1, 70% cured; resection with CCNU and TP-1, 100% cured (last two groups significantly different from resection only). The results indicate a profound effect of TP-1 in prolonging life and increasing cure of tumor-bearing mice. This effect was manifested when tumor load was small and was apparently more pronounced on metastatic than on primary tumor.

Reactive oxygen intermediates and serum antioxidative system in patients with chronic C hepatitis treated with IFN-alpha and thymus factor X.

INTRODUCTION: In this study, the chemiluminescence (CL) of peripheral blood polymorphonuclear leukocytes (PMNLs) and the serum total antioxidative system (TAS) were assessed in patients with chronic C hepatitis (CCH) before and after 3 and 6 months of treatment with interferon (IFN)-alpha and thymus factor X (TFX). MATERIAL/METHODS: The study included 26 patients with CCH aged between 25-63 years (mean: 42.67). Combined therapy with IFN-alpha 2a and a TFX preparation was applied. PMNL metabolic activity was assessed applying the whole-blood CL method. We measured CL response of neutrophils unstimulated and stimulated by opsonized zymosan, N-formyl-methionylleucyl-phenylalanine (N-fMLP), and phorbol-myristate-acetate (PMA) without and after priming with tumor necrosis factor alpha (10 ng/ml). The assessment of serum TAS was performed directly before the beginning of therapy with IFN-alpha and TFX and after 3 and 6 months of the treatment. A colorimetric method based on the reduction of the cationic radical ABTS*(+) (cation 2, 2'-azido-bis-[3-ethylobenzothiazolino-6-sulfonate]) in the presence of serum antioxidants was used. RESULTS: As a result of the treatment with IFN-alpha and TFX, the formation of free oxygen radicals by resting (unprimed) neutrophils increased statistically significantly both without stimulation and following stimulation by fMLP and PMA. A statistically significant increase in the serum antioxidant capacity was observed, which suggests the induction of compensatory processes. CONCLUSIONS: Increased in vitro reactive oxygen species production by both stimulated and unstimulated peripheral blood neutrophils of patients with CCH was observed. Treatment with IFN-alpha and TFX resulted in a compensatory increase in serum antioxidative capacity.

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.

A randomised study comparing granulocyte-colony stimulating factor (G-CSF) with G-CSF plus thymostimulin in the treatment of haematological toxicity in patients with advanced breast cancer after high dose mitoxantrone therapy.

54 patients with advanced breast cancer were randomised into a prospective, non-blinded, controlled trial to receive: mitoxantrone 28 mg/m2 intravenous day 1 and granulocyte-colony stimulating factor (G-CSF) 5 micrograms/kg/day subcutaneously days 2 to 16 (n = 27) or the same regimen plus thymostimulin (TS) 50 mg/day intramuscular at days 2 to 16 (n = 27). The median time to reach a neutrophil count greater than 0.5 x 10(9)/l was lower in the G-CSF+TS treated group (9.13 versus 3.24 days; P < 0.0005). More patients experienced neutropenic fever in the G-CSF group than in the G-CSF+TS group (59.3% versus 22.2%, P = 0.0119). The incidence, duration and severity of clinically or bacteriologically documented infection were lower in patients who received TS. 16 patients (59.3%) in the G-CSF group contracted infection, and 4 patients (14.8%) receiving G-CSF+TS (P = 0.0016). These data indicate that the combination of G-CSF and TS is well-tolerated and may enhance haematological recovery following myelosuppressive chemotherapy in patients with advanced breast cancer.

Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic irradiation? Results of a double-blind randomized trial.

PURPOSE: Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic radiotherapy? MATERIAL AND METHODS: Fifty-six patients with an indication for adjuvant pelvic irradiation after curative surgery were double-blind randomized. All patients took 3 x 4 capsules study medication daily during radiotherapy. Twenty-eight patients in the enzyme group (EG) received capsules containing papain, trypsin and chymotrypsin, 28 in the placebo group (PG) received placebo capsules. All patients were irradiated with 5 x 1.8 Gy weekly to 50.4 Gy using four-field-box technique after CT-based planning. Primary objective was the grade of diarrhea, nausea, vomiting, fatigue and epitheliolysis during radiotherapy. Secondary objectives were the number of supportive medications and treatment interruptions due to acute toxicity. RESULTS: None/mild diarrhea: 43% EG, 64% PG. Moderate/severe diarrhea: 57% EG, 36% PG (P = 0.11). Mean duration: 11 days in EG, 10 days in PG. None/mild nausea: 93% EG, 93% PG. Moderate/severe nausea: 7% EG, 7% PG. None/mild vomiting: 100% EG, 97% PG. None/mild fatigue: 82% EG, 93% PG. Moderate/severe fatigue: 18% EG, 7% PG (P = 0.23). None/mild epitheliolysis: 75% EG, 93% PG. Moderate/severe epitheliolysis: 25% EG, 7% PG (P = 0.16). Treatment interruption (mean days): 2.44 in EG, 1.46 in PG. Number of supportive medication: 29 in EG, 19 in PG. CONCLUSIONS: The prophylactic use of proteolytic enzymes does not reduce acute toxicities, treatment interruptions and number of supportive medication and therefore does not improve tolerance of adjuvant pelvic radiotherapy.

New perspectives on use of thymic factors in immune deficiency.

Current knowledge on the role of thymic factors in the immune response is inadequate and remains relatively primitive when compared with present technical possibilities for assessing lymphocyte subsets or cytokine interaction. New studies support the potential importance of thymic factors as regulators of immune interactions. Indirect evidence supports the concept that thymic factors may work at the level of IL-2. The functional identity of cells responsive to thymic factors and the relation of observed effects to cytokine network interactions need to be established. The use of thymic factors in the future will depend on the development of criteria to identify appropriate settings in which to use such factors and the implementation of appropriate measures of immune functional response.

Antibiotic treatment of burned patients: an Italian multicentre study.

Antibiotic therapy in burn centres with highly specialized ICUs has reduced the mortality and morbidity in burn and trauma but, in spite of constantly improving supportive surgical and resuscitation methods, infection remains a major problem. Indeed, the clinical experience, as recorded in Europe and the USA, using different antimicrobial drugs and regimens, emphasizes a constantly evolving pattern of pathogenic microorganisms in the wound and in the rest of the patient's body, and their increasing chemoresistance. We report the preliminary results of 559 patients in a large controlled multicentre clinical study (mean age 41.4 +/- 17.8 years and burns covering a mean body surface area of 35.7%), with the collaboration of 13 of the 15 major Italian burn centres. The antibiotic treatment consisted of prophylactic administration of pefloxacin (800 mg i.v. OD for 4 days) for all patients as a first treatment while waiting for an antibiogram, and chemotherapy with teicoplanin (800 mg i.v. OD) together with netilmicin (300 mg i.m. OD) in one or more cycles. At random, half of the patients received thymostimulin (70 mg i.m. OD pro die for the first month and every other day thereafter until discharge from hospital). Of the bacterial pathogens involved in septic complications, 63.3% were Gram-positive (Staphylococcus spp. and Streptococcus spp.). The mortality rate was 15.5%. Pefloxacin chemoprophylaxis was successful in 19.4% of patients and cure or improvement was seen with combination chemotherapy in 66.7% of patients, mainly with only one treatment cycle. The incidence of mortality and sepsis was not significantly influenced by treatment with thymostimulin.

Long-term follow-up of patients with myocarditis and idiopathic dilated cardiomyopathy after immunomodulatory therapy.

The randomized clinical trial with interferon-alpha (IFN) or thymic hormones versus conventional therapy was conducted in patients with myocarditis and idiopathic dilated cardiomyopathy (IDC). We enrolled 180 patients to receive IFN (3-5 million units per day) for 3 months, thymomodulin (10 mg three times per week) for 2 months, or conventional therapy alone. Patients were followed-up for 7 years after the end of treatment. Left ventricular function, exercise tolerance and survival rate were significantly better at long-term follow-up in patients treated with IFN or thymomodulin, than in conventionally treated patients. These results implicate that immune modulating therapy might represent important contribution in the treatment of myocarditis and IDC.

Long-term follow up of patients with dilated heart muscle disease treated with human leucocytic interferon alpha or thymic hormones initial results.

OBJECTIVE: To determine whether giving interferon-alpha or thymomodulin in addition to conventional treatment improves cardiac function in patients with idiopathic myocarditis and idiopathic dilated cardiomyopathy. DESIGN: Single-centre, randomised, open label, parallel group comparison of conventional treatment plus interferon-alpha, conventional treatment plus thymomodulin, and conventional treatment alone. PATIENTS: 38 patients aged 19-54 years (23 men) with biopsy-proven myocarditis or dilated cardiomyopathy. 12 were treated with conventional treatment alone, 13 were treated with interferon-alpha and conventional treatment, and 13 with thymomodulin and conventional treatment. SETTING: Tertiary cardiac referral centre. MAIN OUTCOME MEASURES: Clinical evaluation, echocardiography, and Holter monitoring at baseline, 6 months, and 1 and 2 years. Radionuclide ventriculography at rest and during exercise after 2 years. Endomyocardial biopsy at baseline and after a year if the initial diagnosis was myocarditis. RESULTS: Left ventricular ejection fraction was improved in 21 (81%) of 26 patients after interferon-alpha or thymomodulin administration and in 8 (66%) of 12 conventionally treated patients (P < 0.05) at 2 year follow up. The maximum exercise time was significantly longer at 2-year follow up in patients treated with immunomodulators (mean (SEM) 5.1 (0.6) minutes for interferon-alpha and 5.0 (0.4) minutes for thymomodulin) than in conventionally treated patients (3.3 (0.4) minutes). Left ventricular ejection fraction during exercise (assessed by radionuclide ventriculography) improved in 9 of 12 patients treated with interferon-alpha, 10 of 12 patients treated with thymomodulin, and 3 of 9 conventionally treated patients at 2 year follow up. The electrocardiogram was normal in 21 (88%) of 24 patients after interferon-alpha or thymomodulin treatment and 2 (22%) of 9 conventionally treated patients. At 2 year follow up, 19 (73%) of 26 patients treated with immunomodulators and 4 (25%) of 12 conventionally treated patients had improved their functional class. CONCLUSIONS: The results suggest that treatment of idiopathic myocarditis and/or idiopathic dilated cardiomyopathy with interferon-alpha or thymomodulin induces an earlier and significantly superior clinical improvement than conventional treatment alone.