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PubMed1985

Thymopentin as adjuvant to hepatitis B vaccination. Results from three double-blind studies.

The influence of adjuvant thymopentin therapy on the effect of vaccination with HB-Vax was investigated in three independent double-blind studies in which three different time/dose schedules of the adjuvant therapy were used. The first study was conducted with 30 hemodialyzed patients who had previously been non- or hyporesponders. Forty and 26 nonvaccinated hemodialyzed patients were chosen for the two additional studies. A 50-mg dose of thymopentin or placebo was administered subcutaneously in all studies. In one study, in which only one adjuvant injection was administered simultaneously with each vaccine injection, thymopentin inhibited the antibody response. On the contrary, in the other two studies, in which three injections of adjuvant were administered during the week following the vaccination (in one of these studies three injections were also given before the vaccination), no difference in the effect of vaccination was observed in patients on either placebo or thymopentin. Comparison of the results of the present studies with those of earlier observations emphasizes the importance of time/dose schedules of adjuvant therapy in vaccination.

Adjuvants, Immunologic↗
PubMed1984

Immunomodulation with thymopentin in humans.

The effect of thymopentin administered i.v. or s.c. on the levels of circulating specific IgM and IgG KLH (key-hole limpet haemocyanine) antibodies and non-specific immunoglobulins were measured at weekly intervals in elderly volunteers for three subsequent weeks after vaccination with 500 micrograms KLH. As compared with the placebo group, specific IgM and IgG antibody responses significantly increased in the s.c. treated group, but remained at significantly lower levels in the i.v. treated groups. Increases in non-specific immunoglobulin levels were observed after vaccination in the placebo group; no such increases appeared in the groups treated with thymopentin. The results demonstrate the immunomodulatory effect of thymopentin in humans. It is assumed that, depending on the route of application (which indirectly represents different doses), thymopentin can either stimulate or inhibit immune processes. As an immunomodulator it may represent a new therapeutic tool for immunostimulation as well as for specific immunosuppression.

Adjuvants, Immunologic↗
PubMed1984

Interim results on the clinical effects of i.v. administered thymopentin in active rheumatoid arthritis.

Forty-one patients with active rheumatoid arthritis entered a controlled, double-blind, randomized study; 21 received prolonged i.v. injections (10 min) of thymopentin 50 mg 3 times a week for 3 consecutive weeks; the other 20 received placebo under the same conditions. The groups were comparable at the start of the study. Statistical tests of changes within the treatment groups after 3 weeks showed that the improvement achieved in the thymopentin group was significant (p less than 0.05 or p less than 0.01) for each clinical parameter, except for left-hand grip strength. On the other hand, no significant improvement was observed for any parameter except morning stiffness in the patients on placebo. The intergroup comparison showed significant differences, favouring thymopentin over placebo treatment, in the Ritchie index, scores for swollen joints, assessment of severity of pain and scores for changes in the activity of the disease. Only minor side-effects were experienced in the two treatment groups. The present placebo-controlled double-blind study confirms the previous positive results achieved in open studies, i.e., the beneficial therapeutic effect of prolonged i.v. injections of thymopentin in patients with severe rheumatoid arthritis observed after 3 weeks of therapy. The drug appears to be safe at the dose regimen used.

Arthritis, Rheumatoid↗
PubMed1984

Preliminary results on clinical and immunological effects of thymopentin in AIDS.

In an open study, 10 African patients with AIDS were treated with thymopentin 50 mg i.v. 3 times a week for 2 consecutive months: 1 month by i.v. direct injections and 1 month by 30-min i.v. infusions. In group A there were 6 patients with AIDS-lymphadenopathy characterized by weight loss, chronic fever, generalized lymphadenopathy and OKT-4 to OKT-8 ratio below 0.2. Group B consisted of 4 patients with AIDS and opportunistic infections. Immunological studies performed before, during and after therapy included lymphocyte count, T-cell subsets assessment, study of blastogenic response of lymphocytes to PHA and delayed hypersensitivity skin testing to 5 antigens. In group A, results after thymopentin i.v. direct injections showed a significant increase in OKT-3 and OKT-8 cells. After thymopentin i.v. infusion, blastogenic response to PHA increased significantly as compared with pretherapy values and to the values after i.v. direct injections. At the end of infusion therapy, skin tests became positive for 3 antigens (range 2-4). Furthermore, all 6 patients noted subjective improvement associated with significant weight gain and disappearance of fever. In contrast, in group B the clinical and immunological status worsened during therapy and two patients died from opportunistic infections. This preliminary study suggests that i.v. infusion with thymopentin may be useful in the early phase of the acquired immune deficiency syndrome as it produces symptomatic and immunological improvement.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Some observations on various dose regimens of thymopentin treatment in rheumatoid arthritis.

Eight patients suffering from active rheumatoid arthritis were treated with thymopentin, 50 mg, administered as fractionated intravenous infusion over 10 min 3 times weekly for 3-20 weeks. Seven patients experienced clear-cut amelioration of symptoms and signs after just 2-4 weeks of treatment, and this improvement lasted for 6-8 weeks after thymopentin had been discontinued. Comparable positive results were observed in 2 patients who later continued thymopentin therapy by subcutaneous administration. Several subcutaneous dose regimens were tried; the optimal response appears to be achieved with 100-150 mg three times weekly and 150-200 mg twice a week, respectively. Because the subcutaneous therapeutic approach is more attractive to the patient-and also more practical for the physician-it should be investigated further.

Adjuvants, Immunologic↗
PubMed1989

Immunomodulation with thymopentin: in vitro studies.

Immunomodulation is interpreted as a temporary alert in a certain part of the immune system. The activation of immune competent cells is presented as a possible basic mechanism of this phenomenon. In the absence of a primary stimulus, immunomodulation remains physiologically silent, but it results in a modified immune response if the corresponding targets are being stimulated. For practical reasons it is suggested that distinctions be made between preventive and regulative immunomodulation. The PWM-induced IgG production of PBMCs was used as a model for the demonstration of the modulatory effect of thymopentin in vitro. Depending on the concentration of thymopentin used in the cultures, this pentapeptide can either stimulate or inhibit the induced IgG production. It also influences PGE2 production and catabolism in the cultures stimulated with PWM. Indomethacin abolishes the modulatory effect of thymopentin on IgG production in this model. It is suggested that the possibility of interactions between an immune modulator and therapeutic approaches which can influence the proportions or functions of the corresponding target cells be considered.

Adjuvants, Immunologic↗
PubMed1985

Structural requirements for the biological activity of thymopentin analogs.

Thymopentin, the synthetic pentapeptide Arg-Lys-Asp-Val-Tyr, corresponds to residues 32-36 of the thymic hormone thymopoietin. Thymopentin, like thymopoietin, induces intracellular cGMP elevations in the human T-cell line, CEM. Thymopentin also displaces radiolabeled thymopoietin from a receptor glycoprotein prepared from CEM cells, provided that a nonapeptide corresponding to thymopoietin is added to block thymopoietin binding to an additional binding site. Twenty nine analogs with single position substitutions were synthesized by solid-phase or classical solution synthesis, and are evaluated in these assays. All analogs that were active gave positive effects in both assays. A number of substitutions were tolerated at positions 2, 4, and 5, but there was an absolute requirement for L- or D-Arg at position 1 and L- or D-Asp at position 3 to maintain biological activity.

Amino Acid Sequence↗
PubMed1988

Degradation of thymopentin by human lymphocytes: evidence for aminopeptidase activity.

Thymopentin (Arg-Lys-Asp-Val-Tyr) was shown to be degraded in vitro by human lymphocytes into two main fragments; the tetrapeptide Lys-Asp-Val-Tyr and the tripeptide Asp-Val-Tyr. Degradation products were identified by HPLC and amino-acid analysis. Analysis of the time-course of degradation revealed a 'stepwise' degradative event beginning at the N-terminal. The degradation of thymopentin after the first 10 min, as well as the formation of the tetrapeptide (5-30 min) were essentially curvilinear. Degradation of the tripeptide, was linear. Upon screening a panel of compounds that inhibit enzymatic activity, bestatin, amastatin and 1,10-phenanthroline were shown to be the most effective. Bestatin and amastatin caused an 85-90% inhibition of thymopentin degrading activity with IC50 values of 7.1 x 10(-6) M and 4.5 x 10(-9) M, respectively. 1,10-Phenanthroline completely inhibited the degradative process with an IC50 of 2 x 10(-4) M. When the tetrapeptide Lys-Asp-Val-Tyr was used as the starting substrate, similar IC50 values were seen for amastatin, bestatin and 1,10-phenanthroline. The importance of divalent metal ions in the degradative event was demonstrated not only by the effect of 1,10-phenanthroline, but also by the ability of Zn2+ and Co2+ to reverse the inhibition of 1,10-phenanthroline (at its IC50) to activities near control values (no inhibitor). These data strongly suggest that an aminopeptidase(s) is responsible for the degradative activity.

Aminopeptidases↗
PubMed1997

Stabilized analogs of thymopentin. 1. 4,5-Ketomethylene pseudopeptides.

The pentapeptide, thymopentin (Arg1-Lys2-Asp3-Val4-Tyr5) is known for its activity as an immunomodulating drug, but with limited half-life in plasma. In this first paper of a series of three studies, the synthesis of analogs stabilized at the peptide bond between the C-terminal amino acids via insertion of a ketomethylene moiety is described. N-Blocked pseudopeptides containing Val(k)Phe, Ala(k)Phe, and Val(k)Val units were prepared and attached to chloromethyl Merrifield resin via the carboxy terminal. Removal of the N-BOC group by trifluoroacetic acid was followed by sequential coupling with N-BOC dipeptides of aspartic acid to yield resin-bound N-BOC pseudotetrapeptides. Removal of N-BOC and coupling with N-BOC-r-N-tosylarginine followed by total cleavage of blocking groups and resin by HF afforded the target pseudopentapeptides. The analogs were found to compete favorably with thymopentin for binding to CEM cells, but binding was reduced by about 20-30% on average. All analogs showed significant enhancement of half-life versus thymopentin in mouse serum, but most showed only modest improvement in human serum. Insertion of proline or norleucine at position 2 in the chain caused a substantial increase in half-life (3-4-fold), while N-methylnorleucine conferred complete stability in the analogs.

Adjuvants, Immunologic↗
PubMed1997

Stabilized analogs of thymopentin. 2. 1,2- and 3,4-ketomethylene pseudopeptides.

In this second paper in a series of three studies of stable analogs of thymopentin (Arg1-Lys2-Asp3-Val4-Tyr5), the synthesis of analogs stabilized at peptide bonds 1,2 and 3,4 via insertion of ketomethylene units is described. A tris(carbobenzyloxy)arginyl(k)norleucine pseudopeptide was synthesized and coupled to Asp-Val-Phe-resin units followed by HF cleavage to prepare Arg(k)Nle-Asp-Val-Phe analogs. Preparation of N-BOC Asp(k)Val and N-BOC Asp(k)Ala units followed by coupling to Phe- or Tyr-resin units provided resin-bound pseudotripeptide substrates for attachment of various arginyl dipeptides. Cleavage from the resin afforded 3,4-ketomethylene-stabilized pseudopeptide analogs of thymopentin. The Arg-Lys-Asp(k)Val-Phe and Arg-Lys-Asp(k)Val-Tyr analogs were more strongly bound to CEM cells than thymopentin itself. There was significant enhancement of stability in serum for the analogs, especially those containing Arg(k)Nle or Arg-NMeLys moieties at the 1,2-peptide bond.

Adjuvants, Immunologic↗
PubMed1994

Long-term thymopentin treatment in systemic scleroderma.

A study was carried out to investigate whether thymopentin treatment is capable of inducing changes in the immunological status of patients with systemic scleroderma and to compare any such changes with modifications in clinical condition. Nine patients were given thymopentin, 1 ml in 10 ml saline solution, by slow intravenous infusion 3-times weekly for 5 weeks (cycle). The cycles were repeated at 3-month intervals. Treatment duration ranged from 1 to 5 years. Blood samples were drawn at the beginning and at the end of each cycle and the patients' lymphocytic sub-populations were examined. A control group of 9 comparable healthy subjects were similarly tested. Data analysis showed that a statistically significant decrease of CD16+ and CD25+ lymphocytes compared to pretreatment was already apparent at the end of the first thymopentin treatment cycle. An improvement was found in the clinical condition of 7 of the 9 patients at the end of the follow-up period with a significant correction of unbalanced lymphocytic subsets.

Adult↗
PubMed1987

Thymopoietin and thymopentin enhance the levels of ACTH, beta-endorphin and beta-lipotropin from rat pituitary cells in vitro.

Thymopoietin and thymopentin are well characterized polypeptides influencing immunoregulation by several mechanisms. Proposed as a therapy in diseases with major immune abnormalities such as rheumatoid arthritis, thymopentin improved within 2 weeks some clinical parameters as pain and joint swelling. The hypothesis that this spectacular effect could be mediated through interactions with anti-inflammatory (ACTH) and pain relieving (beta-endorphin) hormones producing cells was tested on the rat isolated pituitary cell model. Thymopentin and thymopoietin can enhance in vitro the levels of ACTH, beta-endorphin and beta-lipotropin in a time- and dose-dependent fashion for physiological concentrations ranging from 10(-12) to 10(-8) mol/l. The action on pituitary cells was restricted to those molecules as no changes occurred in LH, FSH, GH, TSH and PRL levels, after otherwise identical experimental conditions.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Thymopentin loaded microsphere preparation by w/o/w emulsion technique: in vitro/ex vivo evaluation.

Poly-D,L-lactide (PDLLA) and polylactide-co-glycolide (PLGA) microspheres containing thymopentin have been prepared by a water-in-oil-in-water-emulsion/solvent evaporation technique. The goal is to stabilize the active compound thymopentin, and to prolong its therapeutic activity, by embedding the drug in a polymeric matrix. The microspheres obtained have been characterized for their morphology and drug content. In-vitro dissolution tests have been performed on the microspheres. Results show that the type of polymer employed (PDLLA or PLGA) does not seem to affect microsphere morphology, while in-vitro dissolution profiles are greatly influenced by the composition of polymer matrix. Ex-vivo evaluation of PLGA microspheres performed on mouse thymocites shows that biological activity of Thymopentin is maintained after loading into PLGA microspheres.

Adjuvants, Immunologic↗
PubMed2002

[Therapeutic effects of Lamivudine in combination with Thymopentin on chronic hepatitis B].

OBJECTIVE: To explore the efficacy of anti-viral drug in combination with immunoregulatory agent in treatment of chronic hepatitis B. METHODS: Totally 98 patients with chronic hepatitis B were divided at random into 3 groups. In groups A (42 cases) lamivudine was used in combination with thymopentin to treat chronic hepatitis B. Lamivudine or thymopentin was used alone in groups B (38 cases) and C (18 cases), respectively. The dynamic changes in serum parameters reflecting HBV replication and liver function were observed. RESULTS: At the end of the treatments, the rates of negative conversion of HBeA g and positive conversion of anti-HBe in the serum were significantly higher in group A than in group B (P<0.05). There was no significant difference between group A and group C (P>0.05). The rate of negative conversion of HBV DNA was markedly higher in group A than in group C (P<0.05). However, there was no remarkable difference between group A and group B (P>0.05). The changes in parameters of viral replication in 6 and 12 months after the treatments were not significantly different from those at the end of the treatments. The effective rate and total effective rate were markedly higher in group A than in the ther 2 groups. Meanwhile, the rate of ALT normalization of remained higher than 85% in group A. CONCLUSIONS: Lamivudine in combination with thymopentin can exert great and lasting effects on HBV and is effective in normalization of ALT.

Adjuvants, Immunologic↗
PubMed1991

Absence of effects of thymopentin on murine host resistance to Listeria monocytogenes.

The effects of various doses of Thymopentin, the synthetic 5 aminoacid fragment of thymopoietin injected on d -4 and d -1 on murine host resistance to Listeria monocytogenes were tested. The experiments did not reveal any regular dose-effect relationship; i.e. no or only marginal (more often small negative rather than positive) effects were observed on clearance and on resistance neither during the T cell independent first hour or the first 2 days of infection in euthymic or thymus deficient nude mice, nor during the T cell dependent phase after 2 days of infection in euthymic mice. Also survival of mice was not increased in a regular dose-effect relationship with dose ranges of Thymopentin from 0.3 ng-30 mg per 30 g mouse; furthermore, injections of 3 micrograms per 30 g mouse for varying time intervals from -3 days before up to 6 days after infection had no protective effect. Thus Thymopentin apparently does not induce measurable macrophage activation directly or cannot increase macrophage activation mediated by T cells in euthymic mice nor does it induce adequate T cell responses in nude mice to promote improved resistance to Listeria.

Animals↗
PubMed1990

Investigations on cell-mediated immunity in patients with breast and ovarian carcinomas receiving a combination of chemotherapy and immunotherapy with thymopentin.

In 78 patients with breast and 37 patients with ovarian cancer the effect of combined chemo- and immunotherapy with thymopentin (Timunox, Cilag) on different parameters of cell-mediated immunity (leukocyte migration inhibition test, serum level of TNF-alpha, IL-1, interferon-alpha, distribution of lymphocyte subsets) and the clinical course of disease was evaluated and compared to patients receiving only chemotherapy. In cancer patients additionally treated with thymopentin an increase in reactivity in the LMI test and an increase of IFN-alpha serum levels could be observed, whereas serum levels of TNF-alpha and IL-2 and the distribution of T-helper, T-suppressor, total T and natural killer cells did not change. Concerning the clinical course of disease, no significant differences could be observed in patients with disseminated spread of disease, whereas in patients receiving combined chemo-immunotherapy in the course of an adjuvant treatment a benefit was found compared to those receiving only chemotherapy. Thus, it seems that the additional administration of thymopentin in breast and ovarian cancer patients under chemotherapy results in a reduction of immunosuppressive side effects of chemotherapy and a positive effect of the survival time in patients with limited spread of disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Thymopentin induces release of ACTH-like immunoreactivity by human lymphocytes.

Peripheral mononuclear (PMN) cells are known to produce ACTH-like immunoreactivity (ACTH-LIR) in vitro. Based on these findings the aim of this study was to find out whether thymopentin (the active pentapeptide of the native hormone thymopoietin) may stimulate ACTH-LIR production and release by cultured normal human lymphocytes. Thymopentin at concentration of 1 microgram/ml was capable of inducing ACTH-LIR release by normal human PMN cells (median 22 pg/ml) whereas ACTH-LIR inside cells was lower (median 11 pg/10(7) cells). The chromatographic characterization of the eluted material identified the presence of ACTH immunoreactive peptides with the elution characteristics of the precursors 31 K proopiomelanocortin, 22 K ACTH and 4.5 K ACTH, together with higher molecular weight material (greater than 43 K). These data demonstrate that thymopentin induces ACTH-LIR release by human lymphocytes, thus adding a novel factor to those already reported (corticotrophin releasing factor, lipopolysaccharide, viruses) capable of such function.

Adrenocorticotropic Hormone↗
PubMed1989

Immunologic effects of long-term thymopentin treatment in patients with HIV-induced lymphadenopathy syndrome.

The immunologic effects of a year-long therapeutic trial with the synthetic thymic hormone thymopentin were investigated in 29 patients with human immunodeficiency virus--induced lymphadenopathy syndrome. Peripheral T4 and T8 lymphocyte subsets and in vitro immunoglobulin synthesis with pokeweed mitogen (PWM) were monitored before treatment, every 4 months during treatment, and after treatment. Significant increases in circulating T4 cells and a reduction of PWM-induced immunoglobulin suppression were noted in the 21 patients who completed the trial. Furthermore, addition of thymopentin to the in vitro cultures improved the PWM response of T and B cells. After thymopentin treatment, a slight variability of clinical symptoms, including weight loss, diarrhea, night sweats, or a combination of these, was also noted in several subjects.

AIDS-Related Complex↗