Effects of Liposome-Entrapped Muramyl Tripeptide Phosphatidylethanolamine (L-MTP-PE) on the Tumor Growth and Survival of Mice Bearing Syngeneic Tumor in Combination with a Chemotherapeutic or Immunomodulatory Agent.

Antitumor activities of L-MTP-PE (Liposome entrapped myuramyl tripeptide phosphatidylethanolamine) in the combination treatment with chemo- or immune-therapeutic antitumor agents against various syngeneic tumors were tested.Against Meth A fibrosarcoma solid tumor system, L-MTP-PE showed slight but statistically significant elongation of survival days against 5-FU monotherapy in spite of its non-effect on tumor growth, when combined with 5-FU. Against liver metastasis model of M5076 carcinoma, L-MTP-PE showed a tendency of elongation of survival days by its single drug treatment, however, elongation with statistical significance was observed in the combination treatment with 5-FU in comparison with control group.These data suggest that L-MTP-PE seems to elongate the survival days of the solid tumor bearing mice and the liver metastasis model basically due to its saving effect on chemotherapeutic drug-induced immunosuppression. In the combination with an immunotherapeutic agent in mice, TNF production induced by another biological response modifier OK-432 was potentiated when primed with L-MTP-PE. L-MTP-PE also potentiate the antitumor effect of OK-432 possibly through the enhanced production of TNF-α. Combination of L-MTP-PE and OK-432 is considered to be a candidate for a new treatment model for cancer.

[Muramyldipeptide - based compounds in current medicine: focus on glucosaminylmuramyl dipeptide].

The role of immune mechanisms in the pathogenesis of almost all human diseases shown in recent decades, increase in antibiotic resistance and secondary immunodeficiency, aging of the population and widespread use of immunosuppressive drugs and procedures suggest a wider use of immunomodulators in current clinical practice, but the use of most of them limits the lack of knowledge. The most promising compounds for the development as immunomodulating agents and adjuvants for a wide range of vaccines are low molecular weight fragments of peptidoglycan - muramylpeptides. The article describes the mechanisms of action of muramylpeptides, their biological effects and properties of medicines developed on their basis. Special emphasis is placed to glucosaminylmuramyl dipeptide registered in the Russian Federation under the trade name Likopid, which is currently the best - studied drug in its group. The results of Likopid studies when used as a prophylactic and therapeutic agent for infections of various localization in adults and children, for oncological diseases and complications of chemotherapy and radiation therapy, psoriasis, atopic and other diseases are presented. It is emphasized that in diseases associated with human papillomavirus and plaque psoriasis, according to current criteria of evidence - based medicine, Likopid should be classified as drug with level A efficacy (high efficiency in 80-100% of patients). High safety of Likopid in adults and children, including newborns, is noted.

Eficacia y seguridad de mifamurtida en pacientes com diagnóstico de osteosarcoma osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia mapi (metotrexate, doxorrubicina, cisplatino e ifosfamida) / Efficacy and safety of mifamurtide in patients with diagnosis of non-metastatic osteoblastic osteosarcoma without previous systemic treatment, in the context of neoadjuvant chemotherapy with mapi (methotrexate, doxorubicin, cisplatin and ifosfamide)

INTRODUCCIÓN: El presente informe expone la evaluación de tecnología sobre la eficacia y seguridad de mifamurtida, para el tratamiento de pacientes con osteosarcoma (OS) osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia com quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). El osteosarcoma (OS) es un tumor maligno primario del esqueleto y la neoplasia primaria más común del hueso en niños y adultos jóvenes. Representa aproximadamente el 20% de todos los tumores óseos primarios malignos y el 0.2% de todos los tumores malignos. Su curva de distribución en cuanto a la edad es bimodal, con un primer pico en la adolescencia y otro después de los 65 años. La adición de quimioterapia agresiva adyuvante o neoadyuvante a la cirugía há mejorado considerablemente el pronóstico de los pacientes con enfermedad localizada, incrementando la tasa de curación de pacientes con OS en las extremidades y sin enfermedad metastásica evidente de 10-15% a 50-70%. OBJETIVO: El presente dictamen preliminar expone la evaluación de la tecnología sanitaria de la eficacia y seguridad de mifamurtida, para el tratamiento de pacientes com osteosarcoma (OS) osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). TECNOLOGIA SANITARIA DE INTERES: La mifamurtida (Mepact, Takeda) es un compuesto químico biológicamente activo con actividad inmunomoduladora, clasificándose como un adyuvante biológico y perteneciente al grupo farmacoterapéutico de los inmunoestimulantes (36,37) . El compuesto es un derivado totalmente sintético del muramil dipéptido (MDP), el estimulante inmunológico natural más pequeño de las paredes celulares de micobacterias (37) . Al igual que la MDP, la mifamurtida es reconocida por el receptor de reconocimiento de patrones NOD2, localizado en varios tipos de glóbulos blancos, principalmente monocitos y macrófagos. De tal manera, mifamurtida simula una infección bacteriana, resultando en una activación de los macrófagos y un incremento en la producción de TNF-alfa, interleuquina 1, 6, 8 y 12, y moléculas de adhesión (e.g., ICAM-1 y LFA-1). METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad del uso de mifamurtida para el tratamiento de pacientes con osteosarcoma osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). La búsqueda se realizó utilizando las bases de datos: National Library of Medicine (PubMed, 09/2017), Web of Science (WoS, 09/2017), y Centre for Reviews and Dissemination (CRD, 09/2017). Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como The Cochrane Library (09/2017), The National Institute of Health and Care Excellence (NICE, 08/2017) del Reino Unido, The National Guidelines of Clearinghouse (NGC, 08/2017) de los Estados Unidos, The Scottish Intercollegiate Guidelines Network (SIGN, 08/2017) de Escocia, Australian Clinical Practice Guidelines (08/2017), The Royal Children's Hospital Melbourne Practice Guidelines de Australia (08/2017), CMA Infobase de la Canadian Medical Association (08/2017), American College of Physicians Clinical Practice Guidelines and Recommendations (08/2017) de los Estados Unidos, Guidelines International Network (GIN, 08/2017), New Zealand Guidelines Group (NZGG, 08/2017) de Nueva Zelanda, Guía Salud de España (08/2017, 08/2017), y el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC) de México. Esta búsqueda se completo revisando publicaciones de grupos dedicados a la educación, investigación y mejora de la práctica clínica oncológica dentro de América y Europa, como The National Comprehensive Cancer Network (NCCN, 09/2017) de los Estados Unidos, y The European Society for Medical Oncology (ESMO, 08/2017). Por último, se completó la búsqueda ingresando a la página web www.clinicaltrials.gov, para así poder identificar ensayos clínicos en elaboración o que no hayan sido publicados aún, y así disminuir el riesgo de sesgo de publicación. RESULTADOS: se llevó a cabo una búsqueda bibliográfica y de evidencia científica hasta setiembre de 2017 relacionada al uso de mifamurtida en el tratamiento de pacientes con osteosarcoma (OS) osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). Según las guías consultadas para pacientes con OS no metastásico resecable, referentes al uso de mifamurtida como parte del régimen quimioterapéutico MAPI neoadyuvante (pre-operatorio), no existen recomendaciones generales, unicamente algunas hacen mención al uso de mifamurtida en un contexto de adyuvancia (post-operatorio). El único ensayo clínico que evalúa el uso de mifamurtida dentro del régimen quimioterapéutico MAPI, lo hace en un contexto adyuvante, el cual reporta que no hubo una mejora estadísticamente significativa en relación a la sobreviva libre de eventos (HR 0.78, IC 95%: 0.54 ­ 1.2; p=0.22). Por otro lado, si bien se observó una aparente mejora en relación a la sobrevida global (HR 0.71; IC 95%, 0.52 ­ 0.96, valor p no reportado), es de notar que el límite superior del intervalo de confianza es marginal con respecto al valor nulo de no significancia estadística y que el valor p no ha sido reportado. Asimismo, estos resultados son invalidados por i) interacción observada entre mifamurtida y quimioterapia, afectando el análisis marginal del ensayo, ii) falta de poder estadístico para comparar individualmente los cuatro regímenes quimioterapéuticos evaluados, y iii) aparente falta de poder estadístico para evaluar el efecto de mifamurtida a los regímenes quimioterapéuticos sobre la sobrevida global. Actualmente, no se ha identificado ningún estudio publicado o en proceso dirigido a evaluar los efectos de la mifamurtida neoadyuvante en población con diagnóstico de OS no metastásico. Por lo tanto, no existe evidencia respecto a la eficacia y seguridad de mifamurtida en un contexto pre-operatorio. Se requiere de un ensayo clínico que evalúe la administración de mifamurtida, prévio a la resección del tumor, en la población de interés del presente dictamen. CONCLUSIÓN: El Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI no aprueba el uso de mifamurtida para el manejo de los pacientes com diagnóstico de osteosarcoma (OS) osteoblástico no metastásico sin tratamento sistémico en el contexto de neoadyuvancia con quimioterapia MAPI.

Pathomorphosis of experimental infection in mice, infected by Streptococcus pneumoniae, under the effect of immunotropic drugs.

Pathomorphological changes in the organs of animals intranasally infected with Streptococcus pneumoniae were studied under conditions of immunotropic therapy added to antibiotic therapy. The pathomorphosis in the lungs, spleen, and thymus in animals treated with likopid, tinrostim, and roncoleukin was described. A positive time course of the pathological process in experimental animals in comparison with intact animals and animals receiving no immunotropic drugs was demonstrated.

[Methodic approaches to treatment of the chronic generalized parodontitis in elderly and senile patients].

A comprehensive treatment with Likopid of chronic generalized parodontitis in 114 elderly and senile patients was carried out. The state of mechanisms of innate immunity (phagocytosis mechanisms) as well as the profile of proinflammatory cytokines was assessed. The effect of antibiotic-resistant strains of prior microflora on the combined therapy of patients of different age with chronic generalized parodontitis was studied. It is established that due to presence of various types of opportunistic pathogens in patients of different age with parodontitis using the prophylactic antibiotics for the empirical (to determine the antibiotic resistance), a combination of Metronidazole and Lincomycin with the mandatory appointment of immunomodulatory drugs for activation of monocyte-phagocytic system of the patient elderly is most advisable. Use of the drug , "Likopid" significantly improves the results of treatment the elderly and old patients with chronic generalized parodonthitis.

Single high-dose treatment with glucosaminyl-muramyl dipeptide is ineffective in treating ankylosing spondylitis.

Earlier studies have shown that high doses of TNF-alpha increase apoptosis in human autoimmune T-cell clones. Based on these studies, a treatment approach was proposed to reduce or eliminate autoimmune T cells in patients with type 1 diabetes using drugs that temporarily elevate TNF levels. Here, we report the treatment of ankylosing spondylitis patient with a single high oral dose of Likopid (glucosaminyl-muramyl dipeptide), which aimed at increasing the levels of TNF-alpha in order to induce apoptosis of autoreactive T cells. The flow cytometric analysis of blood samples collected before and after treatment demonstrated massive elimination of CD8(+) T cells. However, the treatment did not result in any notable therapeutic effect, and real-time PCR analysis demonstrated that stably expanded T-cell clones that were earlier tracked in this patient were unaffected. This report suggests that the controversial approach to eliminate autoimmune T-cell clones through overstimulation is not effective in treating ankylosing spondylitis.

[Likopid in the complex immunomodulating treatment of patients with sarcoidosis of the lung and intrathoracic lymph nodes]. / Likopid v kompleksnom immunokorrigiruiushchem lechenii bol'nykh sarkoidozom legkikh i vnutrigrudnykh limfaticheskikh uzlov.

AIM: To examine the functional status of the immune system in patients with lung and intrathoracic lymph nodes sarcoidosis and to evaluate the efficiency of immunomodulation alone and in its inclusion in combined treatment of the disease. MATERIALS AND METHODS: 58 patients with the disease of varying severity were followed up. Comprehensive examination, involving clinical, immunological, X-ray, and physical studies, in patients treated with combined immunotherapy was performed. Initial examination revealed mixed immunodefficiency with impaired T- and phagocytic activity. According to the degree of immunological changes, the patients were given immunotherapy, including polyoxidonium, T-activin (or immunophan) injections, a complex of multivitamins and trace elements, and total adaptogens. After partial or complete normalization of an immunogram, all the patients received licopid (two-three 10-day courses, 10 mg/day). RESULTS: The optimal result (as long as 3-year remission) was achieved in the first time diagnosed sarcoidosis who have not taken glucocorticoidal hormones. CONCLUSION: The follow-up shows that addition of licopid is a compulsory component of immunotherapy in this disease; the efficiency of treatment is determined by its multimodality. The courses of therapy should be repeated when immunological indices deteriorated.

Biologic response modifiers in pediatric cancer.

Biologic response modifiers are becoming an important addition to surgery, chemotherapy, and radiotherapy in the management of cancer. As this field of research grows and expands, more biologic response modifiers will be incorporated into therapeutic regimens. By stimulating the immune system to eradicate minimal residual disease, these agents may improve the disease-free and long-term survival rates of patients with a variety of malignancies. The challenge is to incorporate biologic response modifiers into the treatment armamentarium in ways that will maximize their tumorigenicity.

Enhanced resistance to Sendai virus infection in DBA/2J mice with a botanical drug combination (Sinupret).

It was investigated whether the botanical drug combination Sinupret is able to modulate the resistance of mice to a respiratory tract infection with Sendai virus (Parainfluenza viridae) if given prophylactically to the animals. Three doses of Sinupret drops (SD) and Sinupret tablets (ST, p.o.), and two active controls, the chemical secretolytic ambroxol (p.o.) and the immunomodulator Muramyldipeptide (MDP, i.v.) were used. Test and reference substances were applied at days - 3 and -1 before infection, except MDP, which was given once on day--before infection. CD4+ and CD8 + lymphocyte subpopulations were measured after infection as indicators of immunological treatment response. Groups of 20 mice each were infected by intranasal application of Sendai virus under anaesthesia. We found that the 1 x and 5 x human doses of Sinupret drops significantly prolonged the survival times (p < 0.05) compared to placebo. Additionally, ambroxol and MDP were comparably less effective. In all groups, changes in CD4 + and CD8 + T-lymphocyte subpopulations of the peripheral blood were observed, but no clear relationship to the treatment results was seen. It was concluded that Sinupret increases the resistance to an experimentally induced respiratory tract infection in mice. Moreover, the effect of Sinupret was superior to that of an immunostimulant (MDP) and of a synthetic secretagogue (ambroxolhydrochloride).

Study on the reduction of chemotherapy induced neutropenia in mice using glucosaminylmuramyl dipeptide.

Neutropenia is a common and often dose limiting side effect of some chemotherapy regimens. The aim of this study was to investigate the ability of an immunomodulator, glycosaminylmuramyl dipeptide (GMDP, CAS 78113-36-7, romurtide) to reduce chemotherapy induced neutropenia. BALB/c mice were treated with 200 mg kg-1 cyclophosphamide (CY) to induce a reversible neutropenia lasting approximately 6-7 days. There was no change in the duration or depth of neutropenia in mice treated with GMDP for 3 consecutive days (2.5 or 25 mg kg-1) starting the day after CY injection. In addition, at the doses used, the time of administration of GMDP relative to CY did not alter this response. However, a marked neutrophilia compared to controls was consistently observed in all cases. Neutrophil counts of up to 14 times the baseline value were measured 6-7 days after the induction of neutropenia. GMDP had no effect in the absence of CY. Less variation was seen in white cell counts of older non-SPF mice treated with CY. When the activity of GMDP (5 mg kg-1) was compared with G-CSF (granulocyte colony stimulating factor, 100 micrograms kg-1) in these animals, GMDP showed a consistent trend to reduce the length of neutropenia, however, under the conditions tested only G-CSF treatment resulted in a significant reduction in the duration of neutropenia. In the 12-week-old mice, the neutrophilia seen with both G-CSF and GMDP was much smaller than in the 8-week-old mice, and was not significantly different from that in control mice treated with CY alone.

Active specific immunotherapy of metastatic melanoma with an antiidiotype vaccine: a phase I/II trial of I-Mel-2 plus SAF-m.

PURPOSE: To determine the toxicity and immunologic activity of an antiidiotype melanoma vaccine that consists of monoclonal antibody I-Mel-2 (MELIMMUNE-2, IDEC Pharmaceuticals, La Jolla, CA) and an immunologic adjuvant SAF-m. PATIENTS AND METHODS: Twenty-six patients with metastatic melanoma, 17 of whom had previously received chemotherapy, were given 2 mg of I-Mel-2 and either 100 micrograms (n = 6) or 250 micrograms (n = 20) of SAF-m. Antiidiotype vaccine was given intramuscularly (IM) biweekly for 4 weeks, and then bimonthly until disease progression. Human antimurine antibodies (HAMA), anti-I-Mel-2 antibodies, and specific antibody (Ab)3 against the melanoma epitope mimicked by the vaccine were titrated before treatment, biweekly from weeks 4 to 12, and every 4 to 8 weeks thereafter. Computed tomographic (CT) scans of the chest, abdomen, and pelvis and magnetic resonance imaging (MRI) of the brain were obtained before and bimonthly during treatment to evaluate responses. RESULTS: Elevated titers of human antimouse antibodies and anti-I-Mel-2 antibodies were associated with clinical antitumor effect (P = .02 and P = .05, respectively). Ab3 was absent in most patients, but was found in the best clinical responder. Fever, myalgias/arthralgias, fatigue, nausea, and headaches were the most common toxicities. Grade III myalgias/arthralgias and headaches required dose reduction of SAF-m in eight patients at the 250-microgram dose. No treatment-related death occurred. Six patients had an antitumor effect: one complete response in liver and lung, two minor responses, and three stable disease. The patient with a complete response has survived nearly 5 years. CONCLUSION: I-Mel-2 antiidiotype vaccine was safe, tolerated best at the 100-microgram dose of SAF-m, and had immunologic and clinical activity.

Enhancement in vivo of the antiinflammatory and antitumor activities of type I interferon by association with the synthetic immunomodulator murabutide.

The therapeutic efficacy of type I interferon (IFN) has been reported to vary considerably in different indications. The use of the cytokine as adjuvant therapy has been suggested to enhance its efficacy and reduce the toxicity frequently associated with long-term and high-dose administration. In this study, we have assessed the activity of type I IFN in the protection against and treatment of acute hepatitis induced in mice by the administration of concanavalin-A (ConA). At the same time, we have evaluated the efficacy of the synthetic immunomodulator murabutide when administered alone or in combination with type I IFN to protect against ConA hepatitis and in the treatment of tumors in MethA sarcoma-bearing mice. Our results demonstrate a prophylactic effect as well therapeutic effects of type I IFN and of murabutide in the inflammation-mediated model of liver damage. The use of combination therapy presented enhanced efficacy in inhibiting the ConA-induced elevation of plasma transaminases. Both compounds were found to suppress IFN-gamma mRNA accumulation in the livers of ConA treated mice. This activity is discussed with respect to the mechanism of action of the two immunomodulators. In addition, the combination of murabutide with type I IFN exhibited synergistic antitumor activity that was clearly seen in the significant regression of MethA tumors and resulted in almost 50 percent tumor-free mice. The potential clinical application of combination therapies using a cytokine and a safe immunomodulator is analyzed in terms of enhancing the cytokine efficacy and extending its use to new indications.

The schistosomulicidal activity and the production of IL-1 and TNF-alpha by peritoneal macrophages from infected mice and their potentiation by muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) treatment.

Production of TNF-alpha and IL-1 by adherent peritoneal exudate macrophages (APEM) was monitored for 20 weeks in Schistosoma mansoni infected mice in comparison to their schistosomulicidal activity. LPS-triggered IL-1 and TNF-alpha production by APEM peaked 10 weeks post infection (p.i.) and declined thereafter. The schistosomulicidal activity of APEM also peaked after 10 weeks but remained elevated thereafter. Infected mice were also treated with the immunostimulator liposomal muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) 6 or 10 weeks p.i., and their APEM were tested 4 weeks later. APEM from such treated animals showed elevated IL-1 and TNF-alpha production when treatment commenced 6 weeks p.i., while their schistosomulicidal activity increased when treatment commenced either 6 or 10 weeks p.i. The L-arginine inhibitor, NG monomethyl arginine, markedly inhibited the schistosomulicidal activity but not the IL-1 and TNF-alpha production of APEM. Our results show that monokine production increases during the acute phase of infection and declines during its chronic phase, while macrophage schistosomulicidal activity remains constant throughout. Furthermore, TNF-alpha or IL-1 may play a minor role in APEM mediated killing of schistosomula.

Effect of ibuprofen on monocyte activation by liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (CGP 19835A): can ibuprofen reduce fever and chills without compromising immune stimulation?

The purpose of this study was to determine the effects of ibuprofen on the ability of liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) to activate human blood monocytes in vitro. We undertook these experiments because the major toxic side-effects following L-MTP-PE infusion, fever and chills, could be prevented when ibuprofen was given orally immediately before L-MTP-PE infusion. It was therefore important to determine whether ibuprofen interfered with the macrophage-activation properties of L-MTP-PE. Peripheral blood monocytes were isolated from normal donors, then incubated with L-MTP-PE in the presence or absence of ibuprofen. The cytotoxic properties of the monocytes were assessed by a radioisotope-release assay against A375 cells. Ibuprofen at dose levels of 40 micrograms/ml suppressed the generation of the cytotoxic phenotype but did not interfere with the killing process once the cells were activated. Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) production, as well as the mRNA expression of these cytokines, was suppressed by 40 micrograms/ml ibuprofen. Since IL-1 and TNF play a crucial role in the cytotoxic function of monocytes, these findings may explain the mechanism by which ibuprofen inhibited the generation of the cytotoxic phenotype by L-MTP-PE. By contrast, ibuprofen dose levels up to 10 micrograms/ml had no effect on the generation of monocyte-mediated cytotoxicity by L-MTP-PE and no effect on the production, secretion, or mRNA expression of TNF and IL-1. Therefore, we concluded that if ibuprofen is to be used to control the side-effects of L-MTP-PE, blood levels of up to 10 micrograms/ml are desirable. In two of three patients, we determined that an oral dose of 200 mg given immediately before L-MTP-PE infusion could achieve these desired blood levels.

Eradication of hepatic metastases of carcinoma H-59 by combination chemoimmunotherapy with liposomal muramyl tripeptide, 5-fluorouracil, and leucovorin.

We have investigated the effect of a combined chemoimmunotherapy protocol with liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE), 5-fluorouracil (5-FU), and 5-formyltetrahydrofolate (leucovorin) on the growth of hepatic metastases using carcinoma H-59, a liver-homing subline of the Lewis lung carcinoma (P. Brodt, Cancer Res., 46: 2442-2448, 1986). C57BL/6 mice inoculated with the tumor cells via the intrasplenic route received three i.v. injections of liposomal MTP-PE, the first of which was administered 3 days prior to tumor cell inoculation. Chemotherapy with 5-FU and leucovorin at the maximal tolerated doses (30 mg/kg per injection) was initiated immediately after tumor inoculation and continued on alternate days for a total of 4 injections. The incidence of liver metastases in animals which received the combined therapy was compared to that in animals treated with chemotherapy or immunotherapy alone. We found that while the number of liver metastases was reduced in all of the treatment groups as compared to control untreated or placebo-treated animals, the combined effect of 5-FU leucovorin and liposomal MTP-PE was significantly better than that of chemotherapy or immunotherapy alone. This was reflected in a reduced incidence (70% as compared to 100% in all other groups) and in a significant reduction in the number and size of the liver nodules. Our results suggest that the efficacy of 5-FU and leucovorin in the treatment of hepatic metastases could be significantly augmented by the addition of the liposome-encapsulated immunoadjuvant MTP-PE.

[The effect of the immunomodulator glucosaminylmuramyl dipeptide on hematopoiesis in mice with experimental cytopenia]. / Vliianie immunomoduliatora gliukozaminilmuramildipeptida na krovetvorenie myshei s éksperimental'noi tsitopeniei.

Simulation of cytopenia by injection of cyclophosphamide (100 mg/kg) or by exposure to ionizing radiation (4 Gy) was shown to cause in mice similar, by the severity and rate of development, transient inhibition of haemopoiesis which was somewhat more persistent after irradiation. Glucosaminylmuramyl dipeptide applied after the above effects promoted the haemopoiesis recovery.

Anti-stress activity in a muramyl-dipeptide.

N-Acetylmuramyl-L-alanyl-D-isoglutamine and some of its derivatives have been examined for anti-stress activity. Amongst these, N-palmitoylmuramyl-L-alanyl-D-isoglutamine is shown to considerably enhance the capacity of animals to endure various types of stress. This indicates that besides acting as immunomodulators and sleep regulators, muramyl dipeptides may also act as anti-stress agents.