romurtide and Leukopenia

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Animals; Anti-Bacterial Agents; Bacterial Infections; Cytokines; Drug Synergism; Hematopoiesis; Humans; Infections; Leukopenia; Mice; Mycoses; Neoplasms; Virus Diseases

This paper presents a review of studies on the metabolism, pharmacological and clinical properties of a new synthetic muramyl dipeptide derivative N2-/(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl/-N6-stearoyl-L-lysine(MD P- Lys(L18), muroctasin). Due to its effect on the number of peripheral blood leukocytes this compound is expected to be a useful drug for the treatment of leukopenia induced by cancer chemotherapy or radiation therapy.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Animals; Fibronectins; Hematopoiesis; Humans; Leukopenia

We have reported that the bacterial cell-wall skeletons, such as mycobacteria, nocardia, corynebacteria, propionibacteria and listeria, had potent adjuvant activity on immune responses. It was reported that N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) was the minimum structural requirement of adjuvant activity of the bacterial cell-wall skeleton and a variety of MDP derivatives and related compounds were synthesized. Among the synthetic MDP derivatives, we have selected MDP-Lys(L18)(romurtide) as the immunostimulant, by using experimental models for non-specific host resistance against Escherichia coli in mice. Romurtide was shown to have host-stimulating activity against bacterial, fungal and viral infections, cytokine producing activity and the capacity to increase the number of leukocytes and platelets in experimental models. It was also shown that the clinical effectiveness of romurtide on the restoration of the number of leukocytes and platelets of cancer patients treated with chemotherapy or radiation therapy. The mechanism of action of romurtide is discussed.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Animals; Cytokines; Hematopoiesis; Humans; Infections; Leukopenia; Mice; Neoplasms

The most appropriate time for administration was studied based on examination of the total number of leukocytes, differential white blood count, and the number of platelets in 30 cases in which 200 micrograms Romurtide (Nopia) was injected subcutaneously on the day of radiotherapy, 5 times a week, for 2 weeks, totally 10 times because leukopenia was caused during treatment with radiotherapy. It was recognized that the number of leukocytes, mainly neutrophils, increased from 1 week after starting administration of Romurtide to after the completion of administration (2 weeks after administration), except 1 week after completion of administration. The increasing effect in the number of platelets was not recognized, and it had decreased from at the completion of administration to 1 week after the completion of administration of Romurtide. The rate of completion of radiotherapy was 100% without any serious adverse events, but there were 4 cases in which fever was observed. Therefore, it is not very favorable to administer Romurtide immediately after radiation, taking account of the treatment period of radiotherapy. It is also considered that it would be necessary to start radiation after sufficient recovery of the number of leukocytes or increase in their number by using G-CSF preparation in cases in which the leukocyte count has fallen since starting radiation due to the influence of the preceding chemotherapy.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Female; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Neoplasms; Time Factors

The effectiveness of thrice-weekly injection of Romurutide for leukocytopenia due to radiation therapy was analyzed. Twenty-two patients were randomly divided into two groups. Ten of group A cases were injected 3 times per week 10 times (3 weeks) and 12 of group B cases were injected 5 times per week 10 times (2 weeks). White blood cell counts and neutrophil numbers in group A were almost the same as in group B at day-3 and day-8, and those in group A were more than in group B at day-15 and day-22, although there were no statistical significances. Lymphocyte percentages, monocyte percentages and platelet cell counts between groups showed no differences. Injections were stopped in 3 cases due to fever (2 in group A, 1 in group B). The effects were recognized in nineteen cases (excluding above 3 cases). The effect of this thrice-weekly injection method during the injection period was the same or more than with 5 injections/week, and the period of the former was 50% longer. The 3 weekly injection method is more effective for prophylaxis of leukocytopenia.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Injections, Subcutaneous; Leukopenia; Lung Neoplasms; Male; Middle Aged; Neoplasms; Uterine Cervical Neoplasms

Muroctasin, a derivative of muramyl dipeptide (MDP), increases WBC count through induction of the colony stimulating factor (CSF). This action of muroctasin is useful to treat cancer patients with leukopenia on chemotherapy. Urogenital cancer patients were randomized to either a 50 micrograms or 100 micrograms dose group of muroctasin when the WBC count dropped below 3,000/cmm in the first cycle of chemotherapy. The patients were then subcutaneously treated with muroctasin once daily for 6 consecutive days, and restoration of their WBC count determined. Out of the 32 patients who were enrolled in the study, 25, 24 and 23 patients were assessed for safety, usefulness and efficacy, respectively. The 100 micrograms dose was more effective in restoring the WBC count than the 50 micrograms dose based on the evaluation by the physicians. This result was also confirmed when we used the criteria for evaluation of adverse reactions as recommended by the Japanese guidelines for evaluation of efficacy of chemotherapy on solid tumors. Mild fever and reaction at the injection site were noted in 16% (4/25). In conclusion, muroctasin is useful for leukopenia after chemotherapy.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Drug Evaluation; Female; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Multicenter Studies as Topic; Urogenital Neoplasms

N2-[(N-Acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine (MDP-Lys(L18), muroctasin), a derivative of muramyl dipeptide (MDP), is known to promote recovery of peripheral leukocyte and platelet counts by inducing cytokines, especially colony stimulating factor (CSF) in myelosuppression secondary to anticancer therapy. This paper reviews the results of a double-blind comparative study on lung cancer patients, administered either 200 micrograms or 20 micrograms of muroctasin for 6 days post-chemotherapy. It demonstrates the efficacy of muroctasin, at 200 micrograms doses levels only, in promoting early recovery of leukocyte and platelet counts and hence the potential for earlier initiation of chemotherapy cycles. The most common side effect encountered during the study was transient fever.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Antineoplastic Agents; Biological Factors; Cytokines; Double-Blind Method; Humans; Leukopenia; Lung Neoplasms; Neutrophils; Platelet Count; Randomized Controlled Trials as Topic; Thrombocytopenia

N2-[(N-Acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine (MDP-Lys(L18), muroctasin), a derivative of muramyl dipeptide, is known to have the activity to augment the number of white blood cells (WBC) via colony-stimulating factor. Muroctasin has been expected to be applied to leukopenia caused by anticancer chemotherapy. When WBC decreased to less than or equal to 3,000/mm3 after the 1st course of chemotherapy, 131 patients with lung cancer, who were previously classified by the combination regimens of chemotherapy, were enrolled in the study and randomized into 3 groups, 200 micrograms (H), 100 micrograms (L) and untreated control (C) groups. The patients were then subcutaneously treated once daily for 6 consecutive days. WBC and its differential count were measured on Days 4, 7 and 15 after commencement of the study. WBCs in H and L groups were recovered greater than in C group. In WBC differential count, the recovery of neutrophil was prominent in muroctasin treated groups. The portion of immature neutrophil in the bone marrow was also increased by muroctasin treatment. A restorative effect on WBC and neutrophil counts was also confirmed only in the second course of H group. On the other hand, fever and pain in the injected site as side effects were common in the H group and L group in both of courses. In this study, the usefulness of muroctasin in leukopenia was suggested when administered at dosages of 200 micrograms for 6 days.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Aged; Antineoplastic Agents; Bacterial Infections; Blood Cell Count; Bone Marrow; Female; Humans; Leukocyte Count; Leukopenia; Lung Neoplasms; Male; Middle Aged

Muroctasin, a derivative of MDP, is known to augment the number of WBC via colony-stimulating factor. Muroctasin has been expected to be promising for application to leukopenia caused by anticancer chemotherapy. When WBC decreased to less than or equal to 3,000/mm3 after the 1st course of chemotherapy, 131 patients with lung cancer, who were previously classified by chemotherapy combination, were enrolled in the study and randomized into 3 groups, 200 micrograms (H), 100 micrograms (L) and untreated control (C) groups. The patients were then subcutaneously treated once daily for 6 consecutive days. WBC and its differential count were measured on days 4, 7 and 15 after commencement of the study. WBCs in H and L groups showed greater recovery than in C group. In WBC differential count, the recovery of neutrophil was prominent in muroctasin-treated groups. A portion of immature neutrophil in bone marrow was also increased by muroctasin treatment. In the present study, the usefulness of muroctasin in leukopenia was indicated when administered at dosages of 200 micrograms for 6 days.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Leukopenia; Lung Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Random Allocation; Vincristine; Vindesine

The restorative effect of N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine (MDP-Lys(L18), muroctasin), a muramyl dipeptide derivative, was studied in patients with leukopenia associated with anticancer chemotherapy and radiation therapy. The drug was subcutaneously administered to 102 cancer patients in a single doses of 200 or 400 micrograms, and each dosage was given either every day for 6 days or every other day over a 5-day period. White blood cell (WBC) counts were made before, during and after treatment. MDP-Lys(L18) was most effective in patients receiving the drug every day and the 400 micrograms dose was somewhat superior to the 200 micrograms dose in augmenting the WBC population. Overall, the response to MDP-Lys(L18), in terms of the increase in number of WBCs, was good to excellent in 41.6% of patients. MDP-Lys(L18) was considerably more effective in patients with solid tumors than in those with hematological malignancies. The most common side effect was fever, which was dose-dependent, more pronounced with alternate-day dosing, and generally well controlled with antipyretics. The results of this study indicate that MDP-Lys(L18) is useful in improving the WBC count in leukopenic cancer patients treated with anticancer therapy. Considering the efficacy and side effect profiles together, it is suggested that 200 micrograms/day for 6 consecutive days is the optimal treatment regimen.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Body Temperature; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged

Muramyl dipeptide (MDP) and its synthetic derivatives which comes from the major constituent of bacterial cell wall has various biological activities as host defence mechanisms. One of the synthetic MDP derivatives, MDP-Lys (L 18), muroctasin has potent biological activities with less adverse reactions among various MDP derivatives. Muroctasin has proved to be safe to use clinically as the results of phase I clinical study. We attempted to evaluate its clinical usefulness and safety from the view point of restorative activity in leukopenia that was induced by cancer chemotherapy in patients with malignancies. It is concluded that muroctasin is effective as well as useful on the restorative activities against leukopenia in lung cancer patients after cancer chemotherapy, with the optimal daily dosage of 200 micrograms for six times by subcutaneous injections through phase II and phase III clinical cooperative studies in Japan. Supposed mode of action of muroctasin for granulocytosis may be the results of CSF production due to stimulation of macrophage by muroctasin. This first clinical success of restoration of leukopenia in patients with cancer receiving cancer chemotherapy by MDP derivative, muroctasin, might be not only advantageous for cancer chemotherapy and/or radiation therapy but also for preventing infections occurring in compromised host due to neutropenia in cancer patients by means of cytotoxic cancer chemotherapy or irradication.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Antineoplastic Agents; Humans; Leukopenia; Neoplasms

The study was carried out to confirm the effect of MDP-Lys (L 18) on the neutrophil number and function in the patients with lung cancer. The patients were enrolled only in case of leukopenia (equal or less than 3,000/mm3 after anticancer chemotherapy) and subcutaneously given 200 mcg of MDP-Lys (L 18) for 7 days. Mean leukocyte counts were found to be 3,900/mm3 and 5,500/mm3 one day and one week after MDP-Lys (L 18) treatment, respectively. The rate of "markedly effective" and "effective" was 53% (8/15). Chemiluminescence by zymosan showed a significant increase after MDP-Lys (L 18) treatment. However, no change of neutrophil function was observed in the tests of chemiluminescence by phorbol myristate acetate, superoxide (O2-) production, hydrogen peroxide (H2O2) production, chemotaxis, bacterial killing and opsonization. Transient fever was observed in 6 cases and eruption accompanied with one fever case. It was concluded that MDP-Lys (L 18) could prevent infection in cancer-bearing immunocompromised patients by increasing the neutrophil number and function.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Aged; Aged, 80 and over; Drug Evaluation; Female; Humans; Immune Tolerance; Leukocyte Count; Leukopenia; Luminescent Measurements; Lung Neoplasms; Male; Middle Aged; Neutrophils

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adult; Aged; Female; Humans; Leukopenia; Male; Middle Aged; Neoplasms; Radiotherapy

Subcutaneous injection of N2-[N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine (MDP-Lys(L18), muroctasin), a synthetic muramyl dipeptide derivative, favoured recovery of mice from experimental leukopenia induced by cyclophosphamide or by irradiation with X-rays. These effects were observed only when MDP-Lys(L18) treatment occurred after cyclophosphamide injection or X-ray irradiation. Prophylactic treatment resulted in neither preventive nor restorative efficacy on leukopenia. In contrast, glutathione was hardly effective on leukopenia in both models, irrespective of treatment timing. The restorative efficacy of muroctasin was found to be dose-dependent and to be attributable at least to its augmenting effect on colony-stimulating factor production, followed by the marked proliferation and differentiation of myeloblasts towards mature granulocytes in the bone marrow. These beneficial effects of MDP-Lys(L18) warrant further evaluation of its clinical usefulness.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Animals; Bone Marrow; Cell Differentiation; Cell Division; Chemical Phenomena; Chemistry; Colony-Stimulating Factors; Cyclophosphamide; Glutathione; Hematopoiesis; Leukocyte Count; Leukocytes; Leukopenia; Male; Mice; Radiation Injuries, Experimental; Spleen