Use of bleomycetin in malignant testicular tumors and the problem of studying bleomycin analogs

The efficacy of the chemotherapy of 16 patients with metastases of malignant tumors of the testicle was studied. The chemotherapy included vinblastine, platidiam and bleomycetin. The latter was used in a dose of 10 mg daily intramuscularly or as long-term intravenous infusions. As a result of the treatment complete and partial regression of the tumors was observed in 5 (31 per cent) and 4 (25 per cent) patients, respectively. Leukopenia was the main side effect. By present the total doses of bleomycetin had amounted to 250 mg for 4 patients and to 300-350 mg for 7 patients. No signs of pulmonary toxicity were observed with the use of these doses. The problem of clinical studies of bleomycin analogs is discussed.     

Elaboration of the combination of antitumor preparations bleomycetin + 5-fluorouracil + cisplatin

Clinical trials on efficacy and toxicity of combined use of bleomycetin, 5-fluorouracil and cisplatin in patients with disseminated tumor processes were conducted. Two regimens were applied. Regimen I included intravenous administration of cisplatin in a dose of 100-150 mg/m2 on day 1, intramuscular administration of bleomycetin in a dose of 10 mg on days 2-4 and intravenous jet injection of 5-fluorouracil in a dose of 400 mg/m2 on days 2-4. Regimen II consisted of intramuscular administration of bleomycetin in a dose of 10 mg on days 1-3, intravenous jet injection of 5-fluorouracil in a dose of 400 mg/m2 on the same days and intravenous administration of cisplatin in a dose of 100-150 mg/m2 on day 4. The intervals between the courses amounted to 4 weeks. Complete regression of cervical carcinoma relapsing was observed in 1 patient. In 5 patients i.e. 1 with small-cell lung cancer, 3 with squamous cell lung cancer and 1 with metastases of low-differentiated cancer from an undetected focus to supraclavicular lymph nodes the effect was partial. Long-term stabilization of the disease at the background of the treatment for 6-7 months was stated in 3 patients. On the whole the objective response was in 6 out of 22 patients or in 27 per cent. 7 of them were treated with cisplatin in a dose of 150 mg/m2. The regimens of the combined use of 5-fluorouracil, bleomycetin and cisplatin were low toxic. The therapeutic effect showed that the combination was of practical value.     

Clinical evaluation of a bleomycin-group antitumor antibiotic bleomycetin

The efficacy of bleomycetin or bleomycin A5 was studied in 128 patients with different malignant neoplasms. The antibiotic was used as a systemic or intracavitary chemotherapeutic agent. Bleomycetin was effective in 75-80, 81.8, 58.3, 70 and 50 per cent of the cases with disseminated derminogenic tumor of the testicle, squamous cell carcinoma of the head and neck, cancer of the penis, carcinoma of the skin and lymphogranulomatosis, respectively. When used intracavitarily the drug was effective in 41.2 per cent of the patients with cancer of the ovaries and lungs, teratoblastoma of the ovaries, cancer of the mammary gland and sarcoma of the soft tissues. Hyperthermia and focal hyperkeratosis as the adverse reactions were observed in 40.6 and 5.4 per cent of the patients, respectively. No toxicity with respect to the lungs was registered.     

Antineoplastic antibiotics in the combined chemotherapy of squamous cell carcinoma

Sixty five patients with squamous cell carcinoma of various localization at stages III-IV or with severe relapses were subjected to chemotherapy according to 3 schemes: AMB (adriamycin + methotrexate + bleomycin or bleomycetin), 34 patients; AMBP (adriamycin + methotrexate + bleomycetin + platidiam), 17 patients and AMFP (adriamycin + methotrexate + fluorofur + platidiam), 14 patients. The efficacy of the schemes was 35, 17.7 and 43 per cent respectively. The AMB scheme in treatment of the patients with maxillofacial carcinoma resulted in remission in 8 out of 20 cases (40 per cent). Analysis of the adverse reactions to the chemotherapy showed that all the three schemes were relatively low toxic. The AMB and AMFP schemes may be recommended for treatment of patients with disseminated or inoperable forms of epidermoid tumors in oncological departments.     

Use of 5-fluorouracil, bleomycetin and platidiam in combined treatment of localized cancer of the larynx]

Preliminary results of chemoradiotherapy in 30 patients with the larynx cancer T3T4N0M0 are presented. Two treatment schemes were applied. According to scheme I, the treatment was started with chemotherapy with 5-fluorouracil in doses of 1000 mg on days 1, 2 and 3, bleomycetin in doses of 15 mg on days 1, 2 and 3 and platidiam in doses of 120 mg/m2 on day 4 followed by radiotherapy to the total dose of 66 to 70 Gy. Scheme II included two analogous courses of the chemotherapy, one prior to the radiotherapy and the other after irradiation in a dose of 38 to 40 Gy, after a two-week interval the radiotherapy was continued to doses of 66 to 70 Gy. 15 patients were treated in accordance with each scheme. Complete resorption of the tumor was observed in 66.6 and 83.3 per cent of the patients treated according to schemes I and II, respectively. The results showed that the use of 5-fluorouracil, bleomycetin and platidiam in combination with radiotherapy was promising in treatment of patients with local cancer of the larynx.     

Clinical use of rubomycin in neuroblastoma in children]

The results of treatment of 23 children at the age of 7 months to 11 years suffering from neuroblastoma are presented; 22 patients with tumors, relapses or metastases were subjected to the treatment and 1 child was treated prophylactically after radical operation. Four patients were subjected to roentgen therapy in addition to the treatment with rubomycin. The antibiotic was administered intravenously in doses of 0.7--1.5 mg/kg in 1--3 days or daily. The caurse dose (3--12 mg/kg) was determined by the treatment efficiency and the side reactions. The objective effect was observed in 68 per cent of the patients, including the pronounced objective effect (marks 3 and 2) in 41 per cent of the cases. Leucopenia (less than 4000 cells in 1 mm3 of the blood). thrombocytopenia, vomiting (or nousea) and changes in the ECG were registered in 20 (87 per cent), 4,9 and 2 patients respectively. When the results of the treatment were positive, repeated courses of the therapy within 1.5--2 years were carried out; 18 patients died within 4 months to 2 years after the first course of the treatment with rubomycin because of the disease development. No signs of the disease were observed in 4 children with in 3--6 years of observation.     

The results of the use of bleomycin and its analogs in the VAB-6 protocol in treating testicular tumors

Efficacy and toxicity of VAB-6 combinations with bleomycin, bleomycetin or peplomycin were studied in treatment of 77 patients with metastases of germ-cell tumors: testicle tumors in 71 patients and extragonadal tumors in 6 patients. After the chemotherapy complete regression was observed in 37 patients (48.7 per cent). In 44 patients (57.1 per cent) residual metastases after the chemotherapy were resected. The frequency of complete regression after using the VAB-6 combinations with bleomycin, bleomycetin and peplomycin amounted to 58.8, 61.5 and 47.1 per cent respectively. The treatment results depended on the disease extent. When the disease extent was minimal complete regression was observed in 87.5 per cent of the patients. The respective figures for the disease moderate and significant extents were 66.7 and 37.8 per cent. During the average observation period of 22.1 months (7-40 months) 39 patients survived and had no signs of the disease. The combinations markedly differed in their toxicity.     

The so-called partial synchronization in the treatment of malignant lymphomas. A clinical study

In a randomized study the effectiveness of a modified MOPP scheme (CVPP scheme) and a so-called partial synchronisation treatment (vincristine or vinblastine respectively and cyclophosphamide) was compared in 72 patients predominantly pretreated with Hodgkin lymphomas and non-Hodgkin lymphomas. From 49 patients affected with lymphogranulomatosis of stage IIIB and IV, 24 were treated according to CVPP scheme; in 10 of them a complete remission was achieved and in 4 of them a partial remission. 25 patients were treated in the control group with synchronization therapy. In 13 of them a complete remission and in 12 of them a partial remission was achieved. With CVPP therapy the mean remission time amounted to 14.4 months and with synchronization therapy 9.2 months. There was no significant statistical difference. From 23 patients with advanced non-Hodgkin lymphomas of a high malignancy 11 received a therapy with CVPP scheme; 2 of them came into a complete remission and 3 of them into a partial one. 12 patients received a synchronization therapy; 7 of them came into a partial remission. With CVPP therapy the mean remission time amounted to 14.4 months, with partial synchronization therapy--10.8 months. Even in non-Hodgkin lymphomas there was no significant difference between the forms of therapy used. Even a comparison of the two survival times of both forms of treatment does not reveal any significance. Thus, both procedures of treatment seem to be comparable in their therapeutic efficaciousness, even if the number of complete remissions during the treatment with CVPP scheme was greater in our investigations. The assumed lower toxicity of synchronization therapy could not be confirmed by our study. In addition to the controversial synchronization effect, the good efficaciousness of treatment according to the so-called synchronization therapy may be due to sensibilizing phenomena and recruitment phenomena.     

Belomycetin in the combined chemotherapy of testicular tumors

The results of the treatment of 21 patients with testicle tumors of various histological structure, stages III and IV, are presented. The combination of bleomycetin (bleomycin A5), an antitumor antibiotic made in the USSR, with vinblastine and platinum derivatives was used. The antitumor effect was observed in 63 per cent of patients, including 21 per cent of patients with complete regression of tumors. The periods of complete and partial remission were 3--13 and 1--9 months, respectively. The combination is sufficiently effective and may be recommended for the treatment of patients with disseminated malignant tumors of the testicle.     

A trial of using augmentin (amoxicillin/clavulanate) in surgical practice]

The experience with the use of augmentin (amoxycillin/clavulane) in abdominal surgery for prophylaxis of postoperative purulent complications was analyzed. The drug was used in 44 patients after relatively pure operations, 37 of them having various risk factors. In 2 patients (4.5 per cent) of that group postoperative pyoinflammatory complications were recorded. For comparison the results of the prophylactic use of cefoperazone, cefamandole or ceftazidime in the group of 78 patients after relatively pure operations on the abdominal cavity organs were analyzed. Postoperative complications in the latter group amounted to 7.4 per cent (4 patients). The results of the treatment of patients in two groups after contaminated operations were also compared. The patients of one group (41 patients) were treated prophylactically with augmentin in a dose of 1200 mg intraoperatively followed by the drug use in a dose of 600 mg thrice daily for 1 to 2 days after the operation. Postoperative pyoinflammatory complications were recorded in 4 patients of that group (9.7 per cent). 78 patients of the other group were treated prophylactically with ceftazidime or cefoperazone in a dose of 2 g and metronidazole intraoperatively or cefoperazone in a dose of 2 g twice daily and metronidazole in a dose of 500 mg twice daily for 1 to 2 days after the operation. Postoperative infectious complications were recorded in 8 patients of that group (10 per cent). In the group of patients with acute cholecystitis treated with ciprofloxacin in a dose of 400 mg in combination, with metronidazole before the operation and for 1 to 2 days after the operation postoperative complications were recorded in 4 patients (17 per cent).     

Cefepime in the treatment of infection in neutropenic patients]

Cefepime, a fourth-generation cephalosporin, was used in the treatment of 11 febrile episodes in 8 patients with profound neutropenia. The patients were neutropenic because of high-dose chemotherapy with stem-cell rescue or second-line salvage chemotherapy for malignant lymphomas (5 patients) or solid tumors (3 patients). The median duration of grade-IV neutropenia (according to the WHO classification) was 11 days (7 to 14). Cefepime was used as the monotherapy in a dose of 2 g thrice daily. Disappearance of the infection signs was recorded in 8 episodes (73 per cent). In 3 episodes (23 per cent) cefepime was replaced by another drug. The tolerability of cefepime was good and no adverse events were observed with the exception of 1 event of an allergic reaction.     

Effect of Soviet bleomycin-bleomycetin on the body of animals in multiple parenteral administration]

Toxicity of bleomycetin was studied on 3 animal species (rats, rabbits and dogs). The antibiotic was administered intramuscularly and intravenously in various doses for a prolonged period of time. The death of the rats, rabbits and dogs treated with repeated lethal doses of bleomycetin was due to its toxic effect on the kidneys and probably lungs. The level of urea in the blood of the animals before death increased up to 300--400 mg %. Histological examination of the kidneys revealed the picture of glomerulonephritis. The lungs were highly plethoric and showed areas of alveolar collapse and consolidation consisting mainly of the collapsed alveolar epithelium. The liver was not affected by bleomycetin according to both the results of some functional tests and histological examination. tthe blood sugar level after bleomycetin administration was not altered significantly. The changes in the peripheral blood were not pronounced. An increased P wave, decreased R wave and deep S wave were seen on the ECG. Such deviitions may be due not only to the changes in the myocardium but also to the lung affection. When bleomycetiin was used repeatedly in nonlethal doses (1 mg/kg for rats, 1--2 mg/kg for rabbits and 0.25--0.5 mg/kg for dogs), the above changes were less pronounced or not manifested at all. No inhibitory effect on hemopoiesis is an important positive characteristics of bleomycetin, so that it compares very favourably with most other antitumor drugs.     

Winter illness and vitamin C: the effect of relatively low doses.

After their random -llocation to one of three treatment aroups, 622 volunteers received either vitamin C or placebo in a maintenance dose of 500 mg once weekly and a therapeutic dose of 1500 mg daily on the 1st day and 1000 mg on the next 4 days of any illness. Two forms of vitamin C were employed: a sustained-release capsule containing ascorbic acid and a regular tabet containing a mixture of sodium and calcium ascorbate. In the 448 subjects who completed an average of 15 weeks in the study of total of 635 episodes of illness were recroded. Respiratory symptoms were recorded on at least 1 day in 92 per cent of these episodes. There were no consistent or significant differences in the sickness experience of the subjects receiving the sustained-release vitamin capsules compared to those receiving the vitamin tablets, but subjects in both vitamin groups experienced less severe illness than subjects in the placebo group, with approximately 25 per cent fewer days spent indoors because of the illness (P smaller than 0.05). These results are compatible with the belief that supplementary vitamin C can reduce the burden of winter illness, but the intake need not be as high as has sometimes been claimed.     

Purulent complications in the surgical treatment of patients with mouth cancer and their prevention]

Local purulent complications after surgical operations for mouth cancer were recorded in 49 (61.3 per cent) out of 80 cases and were mainly due to associations of 2 or more pathogens. The analysis of the factors influencing the development of the complications showed that there was no reliable increase in the number of the complications in the patients subjected at the first stage to the treatment with various antitumor agents: 17 (53.1 per cent) events in the group of the patients subjected to radiotherapy in a total focal dose of 40 Gy, 8 (72.7 per cent) events in the group of the patients subjected to radiotherapy in a dose of more than 60 Gy, 13 (59.1 per cent) events in the group of the patients treated with antitumor drugs and 8 (66.7 per cent) events in the group of the patients operated at the first stage of the treatment. The incidence of osteomyelitis was significantly higher in the group of the patients subjected to radiotherapy before the operation: 13 (30.2 per cent) events vs. 2 (5.4 per cent) in the group of the patients not subjected to radiotherapy. With increasing of the radiation dose, the incidence of osteomyelitis as well increased: 8 (25.0 per cent) osteomyelitis events in the group of the patients subjected to radiotherapy in a dose of 40 Gy and 5 (45.5 per cent) events in the group of the patients subjected to radiotherapy in a dose of more than 60 Gy. The method of osteosynthesis of the lower maxilla with titanium miniplates was also of great importance. The use of various schemes for antibiotic prophylaxis of wound infection in such patients was equally efficient.     

Rifampicin in the therapy of gonorrheal urethritis in men]

The therapeutic efficiency of benemycin (rifampicin of Polish production), a semisynthetic antibiotic was studied in 96 male cases with gonorrhea urethritis. The antibiotic was used in a dose of 300 mg every 6 hours (2.1--3gm for the treatment course depending on the desease severity). Observation of the patients for 1--2 months showed etiological recovery in 91 (94.8 per cent) out of 96 patients. Postgonorrhea inflammatory processes were observed in 8.7 per cent of the cases. For studying late results of the treatmant 62 patients were observed for 3 to 12 months. Gonococci were isolated from none of the patients. No side reactions were found in the patients treated with rifampicin.     

Toxicity, pharmacokinetics and pharmacodynamics of the Soviet bleomycin, bleomycetin, in a single administration to laboratory animals]

Toxicity of bleomycetin (bleomycin A2) administered intravenously, intraperitoneally, subcutaneously or intramusculary in a single dose to animals was almost identical. On its oral administration bleomycetin was 10--14 times less toxic than on its parenteral use. Rats were somewhat less sensitive to bleomycetin than mice. Bleomycetin had no significant effect on the level of the arterial pressure, respiration, ECG characteristics and elements of the vegetative nervous system in narcotized cats. After a single intravenous or subcutaneous administration to rabbits bleomycetin was detectable in the blood for 4--5 hours. The highest bleomycetin levels were registered in the skin, kidneys and lungs. Bleomycetin was mainly excreted with the urine.     

Clinical study of the therapeutic effectiveness of an ointment consisting of swine leukocytic interferon

The ointment containing pig leukocytic interferon had a pronounced therapeutic effect in herpetic affections of the face skin and genitalia. It prevented eruption, shortened the period of its healing and eliminated subjective sensations. The therapeutic effect was observed in 265 (87.7 per cent) out of 302 patients with recurring Herpes simplex treated with ointment.     

Trial of the clinical use of mithramycin in treating testicular cancer

The data on efficacy of mitramycin, an antitumor antibiotic in treatment of 32 patients with cancer of the testicle are presented. The objectively pronounced effect was observed in 37.5 per cent of the cases, mitramycin being effective in patients with tumors resistant to bleomycin, vinblastin and cis-dichlordiaminoplatinum. Nausea and vomiting were the most frequent side effects of mitramycin use. The hemorrhagic syndrome was recorded in 2 patients. The regimen of the mitramycin intravenous administration in a dose of 25--30 microgram/kg once in 2 days was well tolerated by the patients and may be recommended for the treatment of testicle cancer.     

Use of carminomycin on children and adolescents with osteogenic sarcoma]

The therapeutic effect of carminomycin was studied in clinic at different treatment schemes with respect to 14 children and juvenile patients with osteogenic sarcoma. Pronounced local effect evident from disappearance of the pain and in some cases decrease of the metastatic tumor were noted in the patients with metastases of the osteogenic sarcoma to the bones or relapses of the primary tumor. Subjective improvement and objective effect were observed respectively in 90 and 53 per cent of the patients with metastases into the lungs and pronounced lung symptomatology.     

Erythromycin penetration into the cerebrospinal fluid of patients]

Permeability of erythromycin through the barrier of blood-cerebrospinal fluid in neurosurgical patients after its oral administration in a dose of 300-500 mg and intravenous administration in a dose of 200 mg was studied. The erythromycin was determined after the antibiotic single administration at intervals of 40 minutes to 6 hours. A total of 31 observations were performed. Low penetration of erythromycin into the cerebrospinal fluid of the patients was shown. The administration route (oral or intravenous) practically had no effect on the antibiotic penetration level into the subarachnoidal spaces. The highest liquor levels were observed within the period of 3 to 6 hours after the drug administration. The maximum index of penetration from the blood into the cerebrospinal fluid was about 10 per cent. The erythromycin penetration increased in cases with inflammatory changes in the meninges.