Low-dose subcutaneous recombinant interleukin-2 in advanced human malignancy: a phase II outpatient study

Recombinant interleukin-2 (rIL-2; EuroCetus, Amsterdam, Netherlands) was studied in an outpatient phase II trial in 14 patients with progressive metastatic renal carcinoma, malignant melanoma, and colorectal cancer. Escalating doses of rIL-2 were administered as subcutaneous bolus every 12 hours, starting at 0.3 million U/m2/d. A 100% dose increase occurred at weekly intervals, up to a maximum of 2.4 million U/m2/d. Responding patients or patients with stable disease after 4 weeks of rIL-2 (n = 9) were continued on maintenance therapy at 1.8 million U/m2 of rIL-2 administered once weekly. After 12 weeks of therapy, one renal cell cancer patient had a partial regression in lung metastases. Bolus injection of rIL-2 (1.2 million U/m2) resulted in peak serum levels of 25 to 30 U/ml. Toxicity of this regimen was moderate, with local inflammation at the injection sites, grade I-II (World Health Organization) malaise, nausea and/or vomiting, and fevers in 70% to 100% of patients treated. Thyroid dysfunction was observed in 10 patients receiving subcutaneous rIL-2; four of these patients had laboratory evidence of hyperthyroidism, and one had hypothyroidism. rIL-2-induced toxicity reversed spontaneously after cessation of treatment. In all patients receiving rIL-2, a dose-dependent increase in peripheral blood lymphocyte and eosinophil counts was noted, with a mean of 2.6 and 3.8 x 1,000/microliters after 4 weeks of therapy; mean lymphocyte and eosinophil counts were measured at 2.0 and 2.4 x 1,000/microliters in patients who received prior high-dose chemotherapy, compared with 3.2 and 5.1 x 1,000/microliters in those who did not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effectiveness of the intramuscular administration of high doses of penicillin in treating pneumonia]

Clinical tolerance of benzylpenicillin administered intramuscularly in doses of 2000000--3000000 units every 4--6hours (12000000 units a day) was studied in 253 patients with pneumonia. Satisfactory tolerance of sodium benzylpenicillin and pronounced painfulness at the site of injection of potassium benzylpenicillin were noted. General toxic side effects in the form of asthenia, dizziness, pain in the heart region were observed in a part of elderly patients. The benzylpenicillin serum levels after administration of 2000000 units were 6--10 times higher than those after administration of 200000 units. The efficiency of benzylpenicillin elevated doses was studied in 193 patients. In 101 of them the previous treatment with usual doses of benzylpenicillin, i. e. 200000 units every 4 hours was not sufficiently effective. The elevated doses of benzylpenicillin proved to be effective in 78 per cent of the cases, the effect being observed in all the cases with acute pneumonia, in 88.5 per cent of the cases with neglected state and in 83 per cent of the cases with chronic pneumonia. The therapeutic effect was also observed in most of the patients with benzylpenicillin resistant microflora in the sputum. On the basis of high efficiency of penicillin therapy it was concluded that gram-positive cocci played the main role in pneumonia etiology.     

Antidiabetic action of somatostatin after oral glucose loading: due to suppression of glucagon and growth hormone or of intestinal carbohydrate absorption?

To elucidate the mechanism by which somatostatin lowers blood glucose concentration and insulin requirement following carbohydrate ingestion in insulin dependent diabetic patients (IDDM; n = 6), the amount of insulin required for the assimilation of a 50 g glucose load was determined by means of an automated glucose-controlled insulin infusion system with and without concomitant somatostatin infusion. During the 3 hour period following glucose loading plasma concentrations of glucagon and growth hormone were diminished by somatostatin, as were the rise in blood glucose and insulin requirement (4.0 +/- 1.2 U) when compared with the control study (11.3 +/- 1.5 U; p less than 0.01). With cessation of somatostatin blood glucose levels and insulin requirement rose during the following 2 hour observation period (7.5 +/- 1.2 U) but remained basal during the control study (0.7 +/- 0.6 U; p less than 0.0005). Thus the integrated amounts of insulin required for glucose hormone were temporarily suppressed by somatostatin. It is concluded that the diminished insulin requirement and delayed rise in blood glucose during somatostatin administration after an oral glucose load is not due to its "antidiabetic" action by suppressing glucagon and growth hormone release. Our findings favour inhibition of intestinal carbohydrate absorption as the determining cause for the "antidiabetic" action of somatostatin.     

The effect of benzylpenicillin on the activity of antioxidative enzymes in the erythrocytes and on methemoglobin formation in children

Activity of erythrocyte antioxidative enzymes and the content of methemoglobin were studied in 36 healthy children under preventive treatment with benzylpenicillin and in 65 healthy children of the control group. It was shown that there was relationship between the changes in the activity of superoxidodismutase and catalase and the antibiotic dose and duration of the use. After benzylpenicillin intramuscular administration for 3-4 days (the total dose of 80,000-3000000 units) the catalase activity decreased to 65.6 per cent while the activity of superoxidodismutase did not change. When the antibiotic was used for 1-2.5 weeks (the total dose of 3000000-6000,000 units) the activity of catalase and superoxidodismutase decreased to 53.6 and 82 per cent respectively. Beginning from the 3rd week of the antibiotic use the catalase activity increased to 71.6 per cent while the superoxidodismutase activity did not change and remained at the level of 84.9 per cent. The content of methemoglobin in the children treated with benzylpenicillin was about 3 times higher than that in the controls. The correlation between the activity of the antioxidative enzymes and the content of erythrocyte methemoglobin was inverse: the lower was the enzyme activity, the higher was the content of methemoglobin and vice versa. It was concluded that benzylpenicillin impaired definite balance between single electron reduction of oxygen and antioxidative protection resulting in the antibiotic adverse action i. e. increased methemoglobin formation. The effects of benzylpenicillin should be considered when it is used in combination with oxidants in treatment of children.     

Side effects of antibiotics in rheumatic diseases]

Complications due to antibiotic therapy in rheumatic patients subjected to season bicillin prophylaxis in Minsk within 1965--1975 and in patients with extensive collagenoses were studied. Allergic complications mainly ih the form of allergic reactions in the patients treated with bicillin-3 or picillin-5 were observed in 7.8--16.8 per cent of the patients. Within 10 years 52 cases of anaphylactic shock due to the bicillin use were recorded. Side reactions to antibiotics were observed in 16 (17.3 per cent) out of 92 patients with extensive collagenoses. For prophylaxis of the above complications it is recommended to use rational antibiotic therapy in rheumatic patients, strict registration of allergological states in the anamnesis, testing of microbial sensitivity to the antibiotics.     

Antibiotic resistance dynamics of plasma-coagulating staphylococci isolated from patients in 1970-1975]

Resistance of 2345 strains of plasmocoagulating staphylococci isolated from purulent inflammatory foci of surgical patients was studied with respect to the widely used antibiotics by the method of standard paper discs in 1970--1975. It was noted that the cultures resistant to erythromycin and monomycin were more frequent, i.e. from 24.2 +/- 2.5 to 51.4 +/- 3.4 per cent and from 1.0 +/- 0.6 to 28.0 +/- 2.1 per cent respectively, p less than 0.001 in both cases, while the percentage of the strains resistant to benzylpenicillin and tetracycline steadily increased, i.e. from 69.9 +/- 2.4 to 47.0 +/- 2.3 per cent and from 72.8 +/- 2.4 to 28.4 +/- 2.1 per cent respectively, p less than 0.001 in both cases. The number of the resistant cultures to streptomycin and levomycetin slightly changed and was relatively high (about 50 per cent and more). Direct correlation (mean and pronounced) between the amount of levomycetin, tetracycline, erythromycin or monomycin used per citizen of Minsk and the frequency of the strains isolated from the patients to these drugs was noted.     

Serum penicillin G levels are lower than expected in adults within two weeks of administration of 1.2 million units

When introduced in the 1950s, benzathine penicillin G (BPG) was shown to be effective in eradicating group A beta-hemolytic streptococcus (GAS) for at least 3 weeks after administration. Several studies since the 1990s suggest that at 3–4 weeks serum penicillin G levels are less than adequate (below MIC⁹⁰ of 0.016 µg/ml). We studied these levels for 4 weeks after the recommended dose of BPG in military recruits, for whom it is used as prophylaxis against GAS. The 329 subjects (mean age 20 years) each received 1.2 million units BPG IM and gave sera 1 day post injection and twice more at staggered time points over 4 weeks. Serum penicillin G levels were measured by liquid chromatography/tandem mass spectometry. The half-life of serum penicillin G was 4.1 days. By day 11, mean levels were <0.02 µg/ml, and by day 15<0.01 µg/ml. Levels in more than 50% of the subjects were below 0.02 µg/ml on day 9, and <.01 µg/ml on day 16. There was no demonstrable effect of subject body-surface area nor of the four different lots of BPG used. These data indicate that in healthy young adults serum penicillin G levels become less than protective <2½ weeks after injection of 1.2 million units of BPG. The findings require serious consideration in future medical and public health recommendations for treatment and prophylaxis of GAS upper respiratory tract infections.     

Effect of furosemide on the pharmacokinetics of benzylpenicillin and its penetration through the hematoencephalic barrier in experimental and clinical meningococcic meningitis]

Pharmacokinetics of sodium benzylpenicillin after intramuscular administration in a dose of 250 000 gamma/kg and simultaneous intramuscular injection of furosemid (lazix) in doses of 0.5--1--2 mg/kg was studied in experiments on a model of meningococcal meningitis of rabbits and in clinics on patients with meningococcal meningitis. A pronounced effect of furosemid on pharmacokinetics of benzylpenicillin as dependent on a number of factors was found. Furosemid and meningococcal endotoxin had a synergic effect and decreased benzylpenicillin excretion with urine resulting in prolongation of the antibiotic effect in the blood. An increase in benzylpenicillin blood levels and inflammation of the soft brain membranes increased permeability of the hemato-encephalic barrier for the antibiotic.     

Long Acting Single Injection Caudal Anesthesia—1,208 Obstetrical Deliveries with Mepivacaine

Long acting, single injection caudal anesthesia with mepivacaine was studied in 1,208 obstetrical cases.A 1 per cent solution was used in 671 patients and compared with a 1.5 per cent concentration in 537. No remarkable differences were found between the two groups. The 1 per cent solution provided relief of labor discomfort for from 60 to 180 minutes with an average of 110 minutes. In contrast, the 1.5 per cent solution provided an average of 115 minutes with a range of 80 to 210 minutes.A total volume of 30 ml of anesthetic agent yielded anesthesia to a level of the tenth thoracic vertebra or higher in 91 per cent of patients.Significant alterations in blood pressure were uncommon. About 1 per cent of patients required a vasopressor because of a drop in systolic blood pressure below 80 mm of mercury. Another 8 per cent had a drop of over 20 points in systolic pressure but from high enough levels that they did not require a vasopressor.Toxic effects similar to those of lidocaine were found in slightly more than 1 per cent of cases.This anesthesia requires a higher incidence of operative intervention for delivery.     

Sensitivity to antibiotics of pneumococci isolated from patients with chronic nonspecific pneumonia and bronchitis

Four hundred and twenty two pneumococcal strains isolated from 300 patients with chronic nonspecific pneumonia and bronchitis were studied with respect to their sensitivity to 18 antibiotics within a period from 1982 to 1985. It was shown with the method of serial dilutions on solid media that 91.7, 87.8, 85 and 81 per cent of the isolates were sensitive to benzylpenicillin, ampicillin, lincomycin and cefuroxime, respectively. A significant percentage of the pneumococcal strains had decreased sensitivity to benzylpenicillin (MIC close to the therapeutic concentration). On this basis it was recommended to use lower concentrations of benzylpenicillin (less than 0.25 units/ml) in assay of sensitivity in clinical strains of Pneumococcus.     

Comparison of Serological Response to Doxycycline versus Benzathine Penicillin G in the Treatment of Early Syphilis in HIV-Infected Patients: A Multi-Center Observational Study

Background

While doxycycline is recommended as an alternative treatment of syphilis in patients with penicillin allergy or intolerance, clinical studies to compare serological response to doxycycline versus benzathine penicillin in treatment of early syphilis among HIV-infected patients remain sparse.

Methods

We retrospectively reviewed the medical records of HIV-infected patients with early syphilis who received doxycycline 100 mg twice daily for 14 days (doxycycline group) and those who received 1 dose of benzathine penicillin (2.4 million units) (penicillin group) between 2007 and 2013. Serological responses defined as a decline of rapid plasma reagin titer by 4-fold or greater at 6 and 12 months of treatment were compared between the two groups.

Results

During the study period, 123 and 271 patients in the doxycycline and penicillin group, respectively, completed 6 months or longer follow-up. Ninety-one and 271 patients in the doxycycline and penicillin group, respectively, completed 12 months or longer follow-up. Clinical characteristics were similar between the two groups, except that, compared with penicillin group, doxycycline group had a lower proportion of patients with secondary syphilis (65.4% versus 41.5%, P<0.0001) and a higher proportion of patients with early latent syphilis (25.3% versus 49.6%, P<0.0001). No statistically significant differences were found in the serological response rates to doxycycline versus benzathine penicillin at 6 months (63.4% versus 72.3%, P = 0.075) and 12 months of treatment (65.9% versus 68.3%, P = 0.681). In multivariate analysis, secondary syphilis, but not treatment regimen, was consistently associated with serological response at 6 and 12 months of follow-up.

Conclusions

The serological response rates to a 14-day course of doxycycline and a single dose of benzathine penicillin were similar in HIV-infected patients with early syphilis at 6 and 12 months of follow-up. Patients with secondary syphilis were more likely to achieve serological response than those with other stages.     

E. coli resistance to antibiotics on the material studied and the structure of the antibiotic resistance of the strains]

Standard filter paper discs were used to determine the sensitivity of 943 strains of E. coli isolated in 1970-1974 from patients' purulent-inflammatory foci with respect to benzylpenicillin, streptomycin, levomycetin, tetracycline, erythromycin and monomycin. An increase in the specific weight of the cultures resistant to the 6 drugs from 4.7 +/- 1.7 per cent in 1970 to 16.0 +/- 2.6 per cent in 1974 was observed. Strains resistant to 5--6 antibiotis were more often isolated from the urine (64.6 per cent) and the wound content (48.9 per cent) and rarer from the abdominal cavity exudate (23.1 per cent), bile (28.0 per cent) and sputum (30.1 per cent). Most often certain combinations of resistance to benzylpenicillin, streptomycin, tetracycline and erythromycin were found in the E. coli strains tested.     

Effect of acute and chronic administration of L- thyroxine and methimazole on blood levels of tryptophane, serotonin and 5-hydroxyindoleacetic acid in plasma of rats]

The effects of hyperthyreosis induced by the administration of thyroxine and hypothyreosis induced by the administration of methimazole on the levels of tryptophane, serotonin and 5-hydroxyindoleacetic acid in low-platelet blood plasma have been studied in Wistar rats. Thyroxine administration (120 micrograms/kg/24 h, intraperitoneally) lasting 7 days caused a decrease in serotonin concentration by 38 per cent. The level of this amine in rats receiving thyroxine during three months was elevated by almost three times. Tryptophane concentration did not change following thyroxine administration. Methimazole administration lasting 14 days (oral dose 15 mg/kg/24 h) caused an increase in tryptophane concentration by 34 per cent and in serotonin concentration by 24 per cent. Long-term hypothyreosis induced by methimazole administration lasting three months caused an 39 per cent increase in tryptophane and 38 per cent increase in serotonin concentration. Neither hyperthyreosis induced by thyroxine administration nor hypothyreosis induced by methimazole++ caused any changes in the concentration of 5-hydroxyindoleacetic acid. The importance of serotonin in pathogenesis of clinical symptoms accompanying the states of deficit or excess of thyroid hormones needs further elucidation.     

Subcutaneous interleukin-2 and interferon-alpha 2b in patients with metastatic renal cell cancer: the German outpatient experience

A phase II clinical trial was conducted using subcutaneous recombinant human interleukin-2 (rIL-2, EuroCetus) and subcutaneous interferon-alpha 2b (rIFN-alpha 2b, Essex) in patients with advanced cancer. Safety and tolerance of this outpatient regimen were assessed in 17 patients with progressive metastatic renal carcinoma, 14 of whom were evaluable for clinical response to combined rIL-2 and rIFN-alpha 2b. In this study, rIL-2 was administered every 12 hours, at 1.5 million (Cetus) U/m2 on days 1 and 2, followed by 0.3 million U/m2 5 days per week for 6 consecutive weeks. Concomitantly, rIFN-alpha 2b was given as 5 million U/m2 three times weekly for 6 consecutive weeks. Patients presenting with stable or regressive disease after 6 weeks of rIL-2 and rIFN-alpha 2b (11 of 14) were scheduled to repeat combination therapy. After one treatment cycle, five of 14 patients presented with partial remission; two of these patients achieved complete regression of metastatic lesions. After therapy, six patients have been in stable disease for up to 8 months. toxicity of this regimen was moderate, with local inflammation of the injection sites, grade I-II (World Health Organization criteria) fevers, chills, malaise, nausea and/or vomiting, and anorexia in 70% to 100% of patients treated. After 6 weeks of rIL-2 and rIFN-alpha 2b, laboratory evidence of treatment-related hypothyroidism and hyperthyroidism was obtained in one and four patients, respectively. Immunogenicity of sc rIL-2 was mostly limited to the development of nonneutralizing antibodies that occurred in approximately 40% of patients. None of the patients exhibited antibodies specific to rIFN-alpha 2b.     

Effect of antibiotics on the absorption of basic nutrients]

The impact of tetracycline, gentamicin, streptomycin, erythromycin, oxacillin, benzylpenicillin and sulfanilamides on the absorption function of the small intestine was studied in 79 patients with chronic bronchitis. The drugs were shown to mainly inhibit fat absorption: on the average, by 87 per cent in all the patients treated with tetracycline, on the average, by 89 and 36 per cent in 80-70 per cent of the patients treated with gentamicin and streptomycin, respectively, and, on the average by 26 and 16 per cent in 20-25 per cent of the patients treated with erythromycin and oxacillin, respectively. The absorption of protein decreased, on the average, by 23-74 per cent in all the patients treated with tetracycline, gentamicin and streptomycin. As for the other drugs, they had, on the average no significant effect on protein absorption. The absorption of carbohydrates (d-xylose) significantly decreased under the effect of these three drugs (by 21, 34 and 36 per cent, respectively). The analysis revealed a relation of absorption function to the presence and degree of intestinal dysbacteriosis.     

Effect of sulfalene and furosemide on benzylpenicillin kinetics in rats with aseptic inflammation

The effect of sulfalen and furosemide on benzylpenicillin kinetics in blood serum, intact tissues and aseptic inflammation foci was studied on rats. It was shown that under the action of sulfalen and furosemide protein binding of benzylpenicillin lowered by 30 per cent. The changes in the antibiotic kinetics after combined use with sulfalen and furosemide were of the same type: markedly increased concentrations in blood serum and tissues and retarded elimination.     

ELECTRON MICROSCOPICAL STUDY OF SKELETAL MUSCLE DURING ISOTONIC (AFTERLOAD) AND ISOMETRIC CONTRACTION

Bundles of the curarized semitendinosus muscle of the frog were fixed during isotonic (afterload) and isometric contraction and the length of the A and I bands investigated by electron microscopy. The sarcomere length, during afterload contraction initiated at 25 per cent stretch, varied depending on the afterload applied between 3.0 and 1.2 µ, i.e. the shortening amounted to 5 to 50 per cent. The shortening involved both the A and I bands. Between a sarcomere length of 3.0 to 1.7 µ (shortening 5 to 35 per cent) the A bands remained practically constant at about 1.5 µ (6 to 8 per cent shortening); the length of the I bands decreased from 1.4 to 0.3 µ (80 per cent shortening). Below a sarcomere length of 1.7 to 1.2 µ the A bands shortened from 1.5 to 1.0 µ (from 6 to 8 to 25 per cent). At sarcomere lengths 1.6 to 1.2 µ the I band was replaced by a contraction band. During isometric contraction the A bands shortened by about 8 to 10 per cent; the I bands were correspondingly elongated.     

Effect of electrophoresis of the head region on benzylpenicillin penetration across the blood-brain barrier

A procedure for administration of sodium benzylpenicillin (SB) to the brain was developed and tested on 22 rabbits. SB was administered drop-like intravenously in a dose of 200,000 units/kg body weight in combination with electrophoresis of the head area. It was shown spectrophotometrically that a single administration of SB increased its concentration in the liquor and brain tissues by 366.7 and 500 per cent respectively as compared to the control values. Practically no shifts in the EEG and ECG were observed which was indicative of safety of SB administration by that route. The procedure for intraorgan administration of SB in combination with electrophoresis may be recommended for clinical use.     

Production of toxic shock exotoxin by Staphylococcus aureus strains resistant and sensitive to antibiotics

Three hundred and ninety two strains of S. aureus isolated from bacteria carriers and patients with staphylococcal infections in different regions of the Soviet Union were investigated. 55.9 per cent of the isolates were able to produce exotoxin of toxic shock. No regular relation between resistance to definite antibiotics (tetracycline, chloramphenicol, benzylpenicillin, streptomycin, lincomycin, erythromycin, oleandomycin, gentamicin and methicillin) and the polyresistance range on the one hand and the ability to produce toxic shock exotoxin on the other hand was revealed.     

Concentration of acid phosphatase,ribonuclease, desoxyribonuclease,beta-glucuronidase,and cathepsin in droplets isolated from the kidney cells of normal rats

1. Three fractions of "droplets" having diameters of 1 to 5 micro (fraction I), 0.5 to 1.5 micro (fraction II), and 0.1 to 1.0 micro (fraction III) were isolated from the kidney cells of normal rats. 2. All three "droplet" fractions showed 10 to 15 times higher activities of acid phosphatase, beta-glucuronidase, ribonuclease, desoxyribonuclease, and cathepsin than the total homogenate and the mitochondrial fraction. 3. After a rough fractionation of the total homogenate, approximately 50 per cent of the 5 enzymes was found in the fractions which contained the "droplets" and approximately 30 per cent in the supernatant fluid. 4. The similarities between the enzymatic properties of the "droplets" from kidney cells and of the fractions isolated from liver cells by other investigators have been discussed.