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The incorporation of thymostimulin, an immunoactive hormone extracted from calf thymus, into liposomes was characterized by means of DSC analysis. Changes in vesicle composition, as well as in the presence of cholesterol, led to variations in thermotropic behaviour and influenced their incorporation efficiency and stability. Among the prepared formulations, liposomes prepared using equimolar amounts of DPPC and DMPC showed the highest value (80%) for drug incorporation.

To evaluate whether indomethacin (IM) and thymostimulin (TP-1) could revert the alterations of natural killer cytotoxicity (NKC) observed in patients and carriers of Thalassemia Major (TM), 14 TM patients, 10 TM carriers, 16 normal controls, and 4 polytransfused patients were studied. In vitro, IM induced an increase in NKC of normal controls and TM carriers (Δ CI: + 5.98±2.49 and + 9.77±6.82 respectively), but not in TM patients (-0.32±1.45) or other polytransfused recipients. The addition of IM to Concanavalin A (Con A) also resulted in an increase of NKC in normal controls and TM carriers, similar to that induced by each substance separately in normal controls, or by IM alone in TM carriers. Similarly, TP-1 (50 μg/ml) induced increases of NKC in normal subjects (+ 4.66±3.62), but not in TM patients (-1.1±2.43). The impairment in NKC observed in TM and polytransfused patients, and the absence of response to Con A in both, TM patients and carriers, do not seem to be mediated by an excessive production of prostaglandins. The lack of response not only to Con A, but also to TP-1 could indicate a quantitative or qualitative defect in T cells, that affects NKC regulation, or a deficient response of NK cells to modulators produced by T lymphocytes.

La evaluación clínica e inmunológica de diez caninos con demodicosis generalizada mostró un patrón de lesiones acorde con la sintomatología descrita para esta enfermedad, constituida en su mayoría por la presencia de zonas alopécicas, prurito y eritema difusos y en menor porcentaje, por lesiones costrosas, ronchas, foliculitis y úlceras. La edad de los pacientes se ubicó entre 5 y 24 meses pudiéndose clasificar como demodicosis de comienzo juvenil. Las razas más afectadas fueron el Pastor Alemán, el Criollo y el Chow-Chow. El 60% de los pacientes fueron machos. La mitad de los animales fueron tratados con Amitraz en 250 ppm (0,025%) y la otra mitad con Timoestimulina Tp-1 Serono. Antes del tratamiento, los valores hematológicos de los caninos infectados se detectaron en su mayoría dentro de los límites normales, pudiéndose observar en algunos, neutrofilia con desviación a la izquierda de tipo regenerativa, eosinofilia y monocitosis. Con el Amitraz se observaron algunos casos de neutrofilia y monocitosis. Leucocitosis, neutrofilia, linfocitosis y monocitosis fueron observados posterior al tratamiento con la Timoestimulina. El tratamiento con ambos medicamentos resultó efectivo entre un 75 y 100% a los 30 días. La prueba de NBT (Nitro Blue Tetrazolium) resultó negativa en todos los caninos infectados. Ambos tratamientos permitieron recuperar la función neutrofílica. Los linfocitos de los pacientes estimulados con mitógenos tales como PHA (Fitohemaglutinina) y Con A (Concanavalina A) con el Test de Transformación Linfoblástica (TTL) mostraron una bala proliferación. Comparados con los controles sanos, la supresión se ubicó en un 74,7% frente a PHA y 85,5% para Con A. El tratamiento con Amitraz no modificó la respuesta proliferativa linfocitaria. Los animales tratados con Timoestimulina mostraron una sobre estimulación frente a ambos mitógenos. Estos resultados sugieren que los caninos con demodicosis generalizada presentan una deficiencia de la inmunidad innata y adaptativa. La recuperación de la respuesta linfocitaria por efecto de la Timoestimufina exclusivamente puede resolver e cuadro clínico de la demodicosis generalizada. Clinical and immunological evaluation of ten canines affected with generalized demodicosis showed a similar lesion pattern described for the disease, such as, alopecic areas, pruritus, and diffuse erithema and in less degree trusts lesions, excoriations, foliculitis and ulcers. Age of all patients was in the range of 5 to 24 months, allowing to classify the disease as demodicosis. The most affected breeds were german shepherd, mongrel and chow-chow. Sixty percent of the patients were males. Half of the animals was treated Amitraz at 250 ppm. (0.025%) and the other half with Thymostimulin Tp-1 Serono. Before treatment, hematological values were found to be in normal ranges in most of the patients, some of them were found to have, neutrophylia with a regenerative left shift, eosinophylia and with a monocytosis. With the Amitraz treatment some cases of neutrophylia and monocytosis were observed. After treatment with Thymostimulin, leukocytosis neutrophylia, lymphocytosis and monocytosis were found. Both treatments were effective at ranges from 75% to 100% after 30 days. Nitroblue tetrazolium (NBT) test was negative in all the infected canines. Both, Amitraz and Thymostimulin treatments recovered neutrophylic function. The lymphocytes of patients stimulated with mitogens such as Phytohemagglutinin (PHA) and Concanavalin A (Con A) with the Lymphoblastic Transformation Test (LTT), showed low proliferation. When compared to healthy controls, suppression was of 74.7% with PHA and 85.5% with Con A. Treatment with Amitraz did not modify the lymphocytic response. The animals treated with Thymostimulin showed an overstimulated response of lymphocytes proliferation on the LTT compared to the rest of the mitogens. These results suggest that canines with generalized demodicosis show an innate and adaptative immunodeficiency. The recuperation of the lymphocytic response by the effect of Thymostimulin can solve the clinical appearance of generalized demodicosis. 145 - 152 amena@cantv.net Bimestral

4519 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 independ...

Background There is little information about the relationship between thymic hormones and atopy. Methods Human thymostimulin was obtained from thymus of children who died in car crashes. These polypeptides were purified by a Sephadex G-50 column fractionation and incubated in vitro with human lymphocytes obtained from atopic and non-atopic subjects of different ages. The SDS-PAGE revealed at least the presence of three broad bands of proteins with 20, 30 and 60 kDa of molecular weight approximately. Levels of IL-4 from lymphocytic cultures were measured by ELISA and correlated with atopic and non-atopic status and with age. The non-atopic controls showed 5.20 UI/ml ± 1.14 UI/ml of IL-4 meanwhile the non-atopic cells stimulated showed 8.15 UI/ml ± 2.438 UI/ml. On the other hand, the atopic cells revealed a spontaneous release of 12 ± 1.812 UI/ml meanwhile those stimulated by the thymostimulin showed 18.53 UI/ml ± 1.40 UI/ml. Results Thymic polypeptides were able to increase the levels of IL-4 in both groups although the atopic subjects showed the greater increase (p > 0.001) independently of their age. Conclusions As it has been suggested that these hormones could be used therapeutically in atopic subjects, our results warn about the adverse effects that could be produced with them.

In this report, we have evaluated the immunological effects following administration of alpha interferon (IFN-alpha) in combination with thymostimulin (TP-1), as well as of IFN-alpha and TP-1 alone in patients with neoplasias who underwent surgery and were subsequently treated with conventional chemotherapy. Data suggest that the combination of IFN-alpha and TP-1 is the most effective in the up-regulation of some immune parameters such as the CD4(+)-CD8+ cell-dependent antibacterial activity. Since this immune function plays an important role in the host protection against different targets such as invading microorganisms and/or neoplastic cells, the administration of TP-1-IFN-alpha is advisable for patients with neoplasias under chemotherapy.

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.

The purpose of the present study is to ascertain the immunorestorative effect of two different drugs on immunodepression induced by small bowel surgical resection in an experimental model. The potential immunorestorative effect has been measured by the ability of the drug to avoid the delay of skin allograft rejection induced by surgery and the inhibition of CD4/CD8 index changes induced by surgery in spleen tissue. 120 Wistar-Furth rats (age 12-16 weeks) anesthetized with a single intramuscular dose of ketamine (25 mg), diazepine (4 mg) and atropine (0.1 mg) were allotted to two main groups. One group received a skin graft (SG) from Fisher 344 rats and was treated with placebo, Inmunoferón (AM-3 polypeptidic drug) or TP-1 (thymostimulin) before the experiment (groups I, II, III) or treated with placebo, Inmunoferón or TP-1 before the experiment and underwent enterectomy and anastomosis (groups IV, V, VI). On the 2nd, 5th and 8th postoperative days, biopsies of the SG were taken and the signs of rejection were microscopically studied and evaluated by a pathologist as zero, incipient, moderate or massive. The other group was treated similarly, but the animals did not receive a SG and were splenectomized 5 days later. CD4 and CD8 lymphocyte subpopulations were identified by means of immunoperoxidase technique and monoclonal antibodies. Thymostimulin is able to stimulate the presence of SG rejection signs on the 2nd postoperative day in nonenterectomized animals and on the 8th postoperative day in nonenterectomized animals and on the 8th postoperative day in enterectomized rats and is able to avoid the decrease of the CD4/CD8 index in spleen tissue after surgical immunodepression.(ABSTRACT TRUNCATED AT 250 WORDS)

The Bursa of Fabricius of 15 day, 1-, 3-, and 6 month-old adult chickens (White Leghorn strain) were studied by histological and histochemical staining, histoenzymatic reactions (LDH, SDH, a-GPDH, NAD, NADPH, Ca++-dependent ATP-ase, pH 8.5) and by anti-thymostimulin immunoreaction. Positive reactions for mucopolysaccharides and enzymatic activities were located in the epithelia of the follicles, i.e. in follicleassociated- epithelium (FAE), inter-follicle-epithelium (IFE) and in different epithelial compartments of cortical and medullary zones. Positive reaction for thymostimulin-like (TSlike) substance was restricted to FAE cells and weakly to the basal lamina of IFE. In 6-month-old chickens, the FAE cells disappeared; the phenomenon of bursal regression was evident, although not all the follicles were involved. In the few still normal follicles, the good reactivity to the enzymes tested suggests that residual physiological activity is still present, even if reduced.

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.

Summary This article demonstates the positive effect of thymostimulin (TP-1) on leucolymphopoiesis in dogs, based on its apparent ability to counteract the immunodepression induced by cyclophosphamide chemotherapy. Thymostimulin administered to healthy cyclophosphamide-treated dogs prevented the initial drop in the values of leucocytes and lymphocytes due to the chemotherapy and restored these values to the higher levels existing before the treatment. In a control group given a placebo instead of TP-1, the immune depression provoked by cyclophosphamide was maintained during all the therapeutic cycles

We describe a case of partial regression of metastatic hepatocellular carcinoma after treatment with thymostimulin. The patient, a 58-year-old man, received no specific therapy for his tumor, but only a thymus extract (« thymostimulin »). At follow-up 6 months later the patient showed clinical improvement, reduction of alpha-fetoprotein level an liver lesions, and a complete regression of lung metastases. The patient died of progression of the disease with 2-year overall survival.

An anti- thymostimulin (TS) serum was tested on calf thymus to study the localization of the hormonal factor. The immunoperoxidase method was applied to tissue fixed in Bouin's fluid and embedded in paraffin, or to tissue fixed in paraformaldehyde and embedded in Epon for semi-thin sections. Immuno-reactivity was shown, with DAB- Fluka , in reticulo-epithelial cells in the medulla, and between the cortex and the medulla, while with DAB-Sigma reactivity was found in the cortex as well. The external cells of Hassall's corpuscles were also reactive. Myoid cells were not reactive. In semi-thin sections a weak reactivity was noted at the periphery of a few lymphocytes. Comparison with the localization of other thymic factors, and the possibility of a functional cycle of the epithelial cells synthesizing one or more factors are discussed.

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.

The in vitro effect of a calf thymus extract, thymostimulin (TP--1), on the E-rosette-forming capacity and on the PHA blastogenic response of peripheral blood lymphocytes was evaluated in 20 patients with untreated Hodgkin's disease. The mean percentage of lymphocytes forming E rosettes increased in patients from 44.2% to 57.5% (P less than 0.005). The mean PHA stimulation index rose with all three concentrations tested, but returned to the normal range only with the highest PHA concentration (60 mu/ml). An increase in the immune parameters was greatest in those patients who presented with decreased E-rosetting cells of total lymphocyte counts or whose disease was Stage III or IV or of mixed cellular histology.

Fifteen Hodgkin's disease patients (8 male, 7 female) aged 19–72 years, who had been in complete unmaintained remission for 1 year or more when the study was initiated, were given 50 mg thymostimulin (TS) IM daily for 60 consecutive days. When compared with 26–30 age- and sex-matched controls, as a group the patients' circulating ENR+, OKT 3 + , and OKT 4 + cells were depressed (0.001≤P≤ .06), whereas their OKT 8 + cell population was not. Low (>1 SD or >2 SD below mean in controls) or borderline (mean value of two subsequent tests >1 SD below mean in controls) values of ENR+, OKT 3 + , and OKT 4 + cells were seen in nine (group I) of the 15 patients tested, while the remaining six patients (group II) had normal T-cell proportions. Following TS treatment, the proportions of ENR+, OKT 3 + , and OKT 4 + cells increased to normal in all group I patients. The T-cell levels, however, decreased to pretreatment values 60–70 days after completion of TS therapy. TS had no effect on the group II patients whose T-cell percentages had initially been normal. Spontaneous cell-mediated cytotoxicity (SCMC) was assessed in 11 patients, and irrespective of the baseline values, there was a significant enhancement (P

The in vivo effect of a calf thymus extract (thymostimulin, TS) on the E-rosetting capacity, PHA blastogenic response, serum migration inhibitory activity (LIF) and skin reactivity to recall antigens was evaluated in 19 untreated patients with Hodgkin's disease. In patients the mean percentage of peripheral blood lymphocytes forming E-rosettes increased from 47 to 55.7% (P ≤ 0.001; normal: 58.9). The mean PHA stimulation index rose with all three concentrations tested but did not reach normal values. Serum LIF was positive in only one patient prior to treatment with a total patient mean LIF of 1.03. Nine patients developed a positive LIF following treatment with a mean LIF for all patients of 0.75 (P ≤ 0.005). Skin tests were positive in ten patients (52.6%) prior to therapy and 18 patients following therapy (94.7%; P ≤ 0.05). Thymostimulin, in vivo, appears to return immunologic competency to a population of untreated patients with Hodgkin's disease.

Even if the pathogenesis of multiple sclerosis (MS) has not yet been clarified, interest is focussed on the role of the immune system in causing the disease-. In recent years many studies have investigated the status of the immune system during MS.

The thymus gland plays a major role in the development and maintenance of host immunity. To this end both thymocytes and thymic epithelium are believed to serve an endocrine function by secreting a family of polypeptide products.1

The effects of hymostimulin on chemotherapy-induced toxicity and long-term survival were studied in 26 evaluable patients with small cell lung cancer. Patients were randomly treated with six cycles of two alternating regimens (cyclophosphamide, 4'-epidoxorubicin, and etoposide; cisplatin and etoposide), with (n = 15) or without (n = 11) thymostimulin (1 mg/Kg i.m., days 7-14 of every cycle). Only complete responders received maintenance treatment, consisting of thymostimulin administered 1 mg/Kg i.m., twice weekly, until tumor relapse. Myelosuppression, fever and documented infectious episodes were significantly less severe in thymostimulin-treated patients, allowing the administration of significantly higher drug doses at shorter intervals between chemotherapy cycles; a significant improvement in complete response rate and survival were also observed. Results suggest that the addition of thymostimulin to standard chemotherapeutic regimens might be of benefit, in view of its favourable effects on toxicity and long-term survival.

The administration of a thymic factor, thymostimulin (TP-1), to mice resulted in considerable augmentation of natural killer (NK) cell activity as measured in a short-term assay against 51Cr-labeled YAC-1 target cells. Conditions suitable for detection of the thymostimulin-induced boosting of NK included multiple daily exposures to TP-1 (50 micrograms/kg), and peak levels of reactivity were observed at 2-4 days after discontinuation of treatment. A strict age-dependency of the effect was also observed, with optimal augmentation of NK-cell activity when TP-1 was administered to mice at 4-6 weeks of age. The effect was not limited to TP-1 treatment but was also observed on administration of another thymic factor (thymosin alpha 1). The activated cells responsible for the increased natural cell-mediated cytotoxicity appeared to be typical murine NK cells, judging by both functional and antigenic criteria.

The thymus gland is known to be essential for the development and maturation of a properly functioning immune system.1 Converging evidence suggests that this maturational effect is mediated both by the microenvironment of the thymus2 and by remote effects of hormonal factors secreted from the thymic epithelial cells.3,4 Several groups of investigators described the isolation of fully or partially purified thymic factors, i.e., thymosin,5–7 thymic humoral factor (THF),8,9 serum thymic factor (FTS),10,11 thymopoietin12–14 and thymostimulin (TS or TP-1R).15,16 Other thymic factors were described,4,17 but were not thoroughly investigated. Two of the above-mentioned thymic hormonal preparations (thymosin fraction V and TS) contain several active peptides. It is agreed today that the thymus secretes more than one active hormone18 and that the demonstrable pleiotropic activities of such hormones3,4,19,20 have some common and overlapping characteristics in addition to some exclusive and perhaps antagonistic features.18,21

To the Editor.— Thymostimulin (TMS), a calf thymus extract, can be successfully used in the treatment of patients with viral diseases and cell-mediated immune defects. A significant reduction in the number of total circulating T lymphocytes has been observed in patients with psoriasis, while the number of circulating B cells was normal and there was an increase of null cells. 1 In skin, the dermal mononuclear infiltrate consists almost exclusively of T lymphocytes and macrophages. 2 Recently, Baker et al 3 studied the relationship between T-cell populations in blood and in skin of psoriatic patients as well as the correlation with the chronicity, type, and extent of the skin lesions. In blood from patients with guttate psoriasis (GP), the reduction in the number of T lymphocytes was due entirely to a decrease in T helper-inducer (Th) cells. In chronic plaque (CP) psoriasis, both Th and suppressor-cytotoxic T-lymphocyte (Ts) subset were

With the advent of effective chemotherapy and the introduction of megavoltage radiotherapy techniques, the relapse-free survival (RFS) in previously untreated Hodgkin’s disease has been radically prolonged (Faguet and Davis, 1982). It would appear that the prolonged RFS is, to various degrees, dependent on age, histological subtype, presence of constitutional symptoms, and extent of disease at presentation (Young et al., 1972).

In a small pilot study, thymostimulin (TP-1) produced tumor regression in almost 50% of patients with hepatocellular cancer (HCC) who were treated with TP-1 alone. However, the mechanism of the TP-1-mediated antitumor effect against HCC is unknown.Human hepatocytes and Kupffer cells were isolated from liver biopsy specimens by collagenase infusion and counterflow elutriation. Hepatocytes and Kupffer cells were incubated in vitro with clinically relevant doses of TP-1. Cell-free supernatant levels for a panel of growth factors and monokines were determined by enzyme-linked immunosorbent assay. The cytotoxic activity of TP-1 alone of TP-1-stimulated hepatocyte and Kupffer cell supernatants against Hep G2 and Hep 3B human HCC cells in vitro was measured by MIT assay.Doses of TP-1 up to 100 micrograms/ml produced no cytotoxicity against Hep G2 or Hep 3B cells. Furthermore, supernatants from TP-1-treated hepatocytes produced no cytotoxicity against Hep G2 or Hep 3B cells, and TP-1 did not stimulate the release of transforming growth factor (TGF)-alpha, TGF-beta, or hepatocyte growth factor. TP-1-treated Kupffer cell supernatants produced significant cytotoxicity against Hep G2 cells but produced no cytotoxicity against Hep 3B cells. Kupffer cells stimulated by TP-1 released significant amounts of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 alpha, and IL-6 compared with control Kupffer cells (p0.01). The activity of TP-1-treated Kupffer cell supernatants against Hep G2 cells was blocked by anti-TNF-alpha antibodies, whereas neither anti-IL-1 alpha nor anti-IL-6 antibodies blocked cytotoxicity.These results demonstrate that TP-1 cytotoxicity against human HCC cells is not mediated directly or through hepatocytes, but occurs through activation of Kupffer cells and release of TNF-alpha. Understanding the mechanism of TP-1 cytotoxicity against human HCC has been used to plan a phase 1 trial of TP-1 combined with regional infusion of doxorubicin to treat unresectable HCC.

A clinical trial was made to evaluate the effectiveness of thymostimulin (TST), a bovine thymic extract, in preventing infections in breast cancer patients treated with polychemotherapy. Fifty-one women treated with adjuvant CMF were randomly divided into two groups: 25 patients received TST plus chemotherapy and 26 patients were subjected to chemotherapy only. Periodic clinical and laboratory checks were performed for at least three months to monitor the occurrence of infections and variations in immunological parameters. Infections (mostly cystitis, conjunctivitis and stomatomucositis) were observed in 37% of the TST treated patients and in 77% of the controls. (p less than 0.005). Serum immunoglobulin concentrations in the two groups were not significantly different, while quantitative analysis of peripheral T lymphocyte subsets showed a higher incidence of decreased T4/T8 ratio in the control group (p = 0.055). Finally, there was a significantly lower incidence of myelotoxicity in the TST treated patients (p less than 0.0005). In conclusion, thymostimulin seems effective in preventing some of the commonest side effects of cancer chemotherapy.