Hydrogen peroxide cream: an alternative to topical antibiotics in the treatment of impetigo contagiosa.

In total, 256 patients with bacteriologically verified impetigo contagiosa were included in three double-blind, parallel group, randomized, multi-centre trials, where the efficacy of hydrogen peroxide cream (Microcid) was compared with that of fusidic acid cream/gel (Fucidin). The trials were performed at 47 centres in three countries, Sweden, Germany and UK, and the results are compiled in the present report. During the course of the 3-week treatment period, 92 patients out of 128 (72%) in the Microcid group were classified as healed, compared to 105 patients out of 128 (82%) in the Fucidin group. This difference was not statistically significant. The reduction in composite sign severity score (the sum of the score for erythema, vesiculation/bullae, weeping and crusting divided by four) in each separate study was 73%, 78% and 84% in the Microcid group and 85%, 85% and 84% in the Fucidin group. No statistically significant differences were found in the separate studies or when compiling the studies in a meta-analysis. When the patients had been classified as healed, beta-haemolytic streptococci were eliminated in all patients treated with Microcid cream. Since treatment started before the result of the bacteriology was known, another 135 patients with negative skin culture were enrolled in the trials, i.e. 391 patients were included in the safety analysis. Out of these, 23 patients reported the occurrence of adverse events, mainly classified as mild. In conclusion, Microcid cream has been documented as a topical alternative to fusidic acid in the treatment of impetigo.

Terbutaline sustained-release tablets in nocturnal asthma--a placebo-controlled comparison between a high and a low evening dose.

The effects of oral treatment with terbutaline sustained-release (SR) tablets (Bricanyl Depot) were studied in nine patients who had bronchial asthma and marked diurnal variation in ventilatory function. In a randomized and double-blind study, the patients were treated with terbutaline SR 7.5 mg b.i.d., terbutaline SR 7.5 mg in the morning and 15 mg in the evening and terbutaline SR placebo b.i.d. Each treatment was given for 1 week. The nocturnal decline in the peak expiratory flow rate (PEFR) was 45% during the placebo period, 27% after the lower and 22% after the higher terbutaline SR evening dose (P less than 0.01 for both treatments compared to placebo). The mean morning PEFR was significantly higher with the high evening dose than with the low evening dose (P less than 0.01). Mild to moderate side effects were noted. The sustained-release preparation of terbutaline seems to be of clinical value in preventing or relieving nocturnal asthma and early morning dipping. The flexible dose technique, with a higher evening dose, results in further improvements in these patients.

Ehrlich ascites tumour cells become refractory to alpha-difluoromethylornithine at a certain stage of growth.

When Ehrlich ascites tumour cells are induced to proliferate by serum stimulation, the ornithine decarboxylase (ODC) activity increases rapidly and reaches two to three peaks during the first 24 h. Inhibition of the first peak in ODC activity (occurring at 4 h) by adding alpha-difluoromethylornithine (DFMO) within 2 h of serum stimulation, results in maximal growth inhibition. Under these conditions, similar degrees of polyamine depletion are achieved. When DFMO is added 3 h after seeding, however, enough polyamines have already accumulated during the initial burst in ODC activity to reduce the antiproliferative effect of the drug. The antiproliferative effect is further reduced when DFMO is added 6 h after seeding. When DFMO is added 23 h after seeding, i.e. after maximal accumulation of polyamines, there is no inhibition of cell proliferation. These findings are important to consider both when designing experimental as well as clinical regimens for this drug.

Comparison between a new once-daily, bronchodilating drug, bambuterol, and terbutaline sustained-release, twice daily.

Bambuterol is a prodrug, from which terbutaline is slowly generated. The objectives of the study were to evaluate whether bambuterol, given once daily, can control symptoms in asthmatic patients and to compare the bronchodilating effect and the side effects with those of terbutaline sustained-release (SR) tablets given twice daily. Twenty-five out-patients with bronchial asthma were treated during two consecutive 14-day periods with either 30 mg bambuterol tablets once every evening or 2 x 5 mg terbutaline SR tablets morning and evening. The study had a double-blind, cross-over and randomized design. The mean evening peak expiratory flow rate (PEFR) (i.e. 24 h after intake of bambuterol and 12 h after intake of terbutaline SR) was significantly (p less than 0.001) higher during bambuterol than during terbutaline treatment (432 vs 415 l/min). The need for beta-adrenoceptor agonist aerosol in the daytime was significantly (p less than 0.05) lower during treatment with bambuterol once daily (0.70 puffs) than with terbutaline SR b.i.d. (1.04 puffs). The type and intensity of the side effects were the same during both treatments.

Terbutaline slow-release tablets in children with bronchial asthma. Effect and pharmacokinetics compared with plain terbutaline tablets.

The effect of terbutaline sulphate in slow-release (SR) tablets (Bricanyl Depot), 5 mg twice daily, was compared with that of terbutaline sulphate in ordinary tablets (Bricanyl), 2.5 mg three times daily, in a double-blind, randomized, cross-over study during 2 consecutive weeks in 10 asthmatic children. Plasma concentrations and urinary excretion of terbutaline were measured at various times during both treatment periods. The SR tablets produced a higher mean plasma concentration in the morning and a smaller peak-trough variation over the day than the ordinary ones. No differences between the two treatments were observed concerning FEV1 (forced expiratory volume in 1 s). Tremor, measured with an opto-electronic tremorgraph, was about the same for two treatments and not significantly different from tremor seen in healthy children. The reported side effects were less frequent in the SR tablet period.

Increased urinary polyamine excretion during liver regeneration.

Tumor growth is a process associated with both cell proliferation and cell death. The increase in polyamine excretion observed in cancer patients may be partly due to leakage of polyamines from proliferating cells, which all contain an elevated polyamine level. However, the increased polyamine excretion may also be due to a release of polyamines from dead or damaged cells. To determine if actively proliferating cells release polyamines, the urinary polyamine excretion was measured during a proliferative event associated with minimal cell necrosis. Rats subjected to partial hepatectomy were used as an experimental model. Their 24-hr urines were collected during 6 consecutive days following the operation. Rat liver regeneration is characterized by a proliferation wave with a maximum 24 hr after the operation. The 24-hr urinary putrescine excretion reached a maximum 2 days after the operation and then decreased. The 24-hr urinary spermidine excretion increased during the second day following operation and remained essentially unchanged during the rest of the experimental period. Although there is an apparent correlation between elevated urinary polyamine excretion and the proliferative activity, concurrent permeability changes and necrotic events may contribute to the increase in polyamine excretion.

Cell cycle phase-dependent induction of ornithine decarboxylase-antizyme.

The activities of ornithine decarboxylase (ODC) and ODC inhibitory protein (ODC-antizyme) were studied in Ehrlich ascites tumor cells, separated according to their position in the cell cycle by centrifugal elutriation. Release and/or synthesis of ODC-antizyme was induced by putrescine treatment. Each mouse received an intraperitoneal injection of 25 mumoles of putrescine at 0, 1, 2, and 3 hr after tumor transplantation. Tumor cells obtained from putrescine-treated and control mice at 4 hr after transplantation were separated into fractions representing all phases of the cell cycle. The cell cycle distribution of the tumor cells in each fraction was determined by flow cytometry. In control tumor cells the ODC activity exhibited two maxima; in late-G1/early-S and in late-S/G2. A marked decrease in ODC activity was observed in mid-S phase. This decrease coincided with maximum ODC-antizyme activity (revealed by putrescine treatment), suggesting that ODC-antizyme is involved in the regulation of ODC activity during the cell cycle.

Ornithine decarboxylase inhibitors increase the cellular content of the enzyme: implications for translational regulation.

Ehrlich ascites tumor cells grown in the presence of inhibitors of ornithine decarboxylase (EC 4.1.1.17) exhibited an elevated content of this enzyme. The increase could not solely be explained by a decrease in the degradation rate of the enzyme. Instead a stimulation of enzyme synthesis, probably mediated via the polyamine-depleting properties of the inhibitors, is suggested. The enhancement of cellular ornithine decarboxylase content was not accompanied by any significant changes in the amount of ornithine decarboxylase mRNA, indicating a regulation at the level of translation.

Development in vitro of the female germ cells of the polychaete Ophryotrocha labronica.

In the polychaete Ophryotrocha labronica each oocyte is during its growth period associated with a single nurse cell. The fact that the oocyte-nurse cell pairs occur isolated in the female coelom makes them easily removable for analysis of their developmental ability in vitro. Using Dulbecco's modified Eagle medium supplemented with amino acids, nucleosides, foetal calf serum and sea water, we have managed to support development in vitro of germ cell pairs from early and mid-oogenesis until maturation of the oocyte, when the nurse cell degenerates and the oocyte enters meiotic metaphase. Radiolabelling of germ cells in mid-oogenesis with tritiated amino acids and uridine during the first day of incubation indicates normal development with synthesis of RNA and protein, and pulses two days later verify a continued normal protein synthesis and yolk formation. The investigation confirms autosynthesis of yolk proteins in the germ cells of this species and indicates a leading role of the nurse cell in the process.

Inhibition of ornithine decarboxylase activity and cell growth by diamines: a comparison between the effects of two homologs, 1,3-diaminopropane and 1,4-diaminobutane (putrescine).

The ornithine decarboxylase (ODC) activity of Ehrlich ascites tumor cells was almost completely inhibited by treatment with either putrescine (10 mM) or 1,3-diaminopropane (5 mM). 1,3-Diaminopropane treatment eradicated the cellular content of putrescine and reduced that of spermidine and spermine. Putrescine treatment caused a dramatic increase in cellular putrescine content and a temporary decrease in spermidine and spermine content. Despite the fact that 1,3-diaminopropane and putrescine inhibited the ODC activity more effectively than did alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ODC, they were considerably less antiproliferative in action. However, as compared to DFMO the diamines were less effective in reducing the total polyamine (putrescine + spermidine + spermine) content of the cells.

Localization of ornithine decarboxylase in mutant CHO cells that overproduce the enzyme. Differences between the intracellular distribution of monospecific ornithine decarboxylase antibodies and radiolabeled alpha-difluoromethylornithine.

The intracellular localization of ornithine decarboxylase (ODC), a key enzyme in polyamine synthesis and cell growth, is a matter of present debate. Using two independent methods of analysis, we have attempted to determine the actual distribution of ODC in a mammalian cell. To overcome the problem of a normally very low cellular ODC content, we have used ODC overproducing mutant CHO cells. These mutant cells exhibit a 10-fold higher ODC activity than do the wild type cells. The localization of ODC protein in exponentially growing cells, was determined by indirect immunofluorescence microscopy (permeabilized whole-cell preparations and 1 micron sections), using a monospecific ODC antibody. The intracellular localization of catalytically active ODC was determined by light and electron microscope autoradiography following pulselabeling of cells with alpha-difluoromethyl(5-3H)ornithine (3H-DFMO) at the time of peak ODC activity. alpha-Difluoromethylornithine (DFMO) is an enzyme-activated irreversible inhibitor of ODC and binds covalently to the active enzyme. The specificity of this reaction in the cell was ascertained by immunoprecipitation of 3H-DFMO-labeled ODC. ODC (as determined by both methods) was present in all the cells of a serum-stimulated monolayer culture. The highest concentration of ODC protein and of catalytically active ODC was observed in the smallest and most rapidly proliferating cells. Polyploid and multinuclear cells always exhibited the lowest concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of the growth inhibitory effect of alpha-difluoromethylornithine by putrescine but not by other divalent cations.

Treatment with alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase (ODC), depletes the putrescine and spermidine content, and reduces the growth rate of Ehrlich ascites tumor cells. The addition of putrescine, which is the immediate precursor of spermidine, promptly replenished the intracellular putrescine and spermidine pools and completely reversed the antiproliferative effect of DFMO. A sequential accumulation of spermine, spermidine and putrescine was observed. 1,3-diaminopropane, a lower homolog of putrescine, did not reverse the antiproliferative effect of DFMO, despite its structural similarity and identical positive charge. By inhibiting remaining ODC activity, resistant to 5 mM DFMO, and possibly by inhibiting spermine synthase activity, 1,3-diaminopropane produced a further decrease in total polyamine content by reducing the spermine content. Mg2+, which can replace putrescine in many in vitro reactions, completely lacked the capacity to reverse the antiproliferative effect of putrescine and spermidine deficiency.

Polyamine starvation prolongs the S and G2 phases of polyamine-dependent (arginase-deficient) CHO cells.

This study analyzes the effects of polyamine starvation on cell cycle traverse of an arginase-deficient CHO cell variant (CHO-A7). These cells grow well in serum-free medium, provided that it contains ornithine or polyamines or both. In the absence of ornithine or polyamines or both, the CHO-A7 cells develop severe polyamine deficiency and, as a consequence, grow more slowly. When grown to a stationary phase in the presence of ornithine or putrescine or both, the CHO-A7 cells became arrested in G0/early G1. However, when starved for ornithine and polyamines, they accumulated in the S and G2 phases. Ornithine and polyamine starvation of CHO-A7 cells causes an increase in ornithine decarboxylase activity. When this increase was prevented by treatment with DL-alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, growth was further suppressed, and a greater fraction of cells were found in the S and G2 phases of the cell cycle.

Urinary polyamine excretion as related to cell death and cell proliferation induced by carbon tetrachloride intoxication.

This study addresses the question whether urinary polyamine excretion is related to cell death or cell proliferation. CCl4 intoxication of the rat was used as the experimental model. Treatment with CCl4, a hepatotoxic haloalkane, produces an initial phase of liver cell death succeeded by a regenerative phase of growth, during which the liver is restored. The highest rate of putrescine (and spermidine) excretion occurred during the first 24 hr of CCl4 intoxication and coincided with the period of maximum liver damage. During subsequent liver regeneration the rate of excretion of both polyamines decreased.

Urinary polyamine excretion during growth and regression of 1,12-dimethylbenz[a]anthracene-induced rat mammary carcinoma.

The correlation of urinary excretion of polyamines and tumor mass was examined with the use of a controlled experimental model. Mammary carcinoma growth was induced in Sprague-Dawley virgin rats by intragastric administration of 7,12-dimethylbenz[a]anthracene. Tumors were palpable after about 45 days. After a period of growth, regression of the estrogen-dependent tumors was induced by bilateral ovariectomy. Tumor volume and 24-hour urinary excretion of polyamines were measured during the course of tumor growth and regression. Urinary polyamines were analyzed after acid hydrolysis to determine the total amount of bound and free polyamines. Putrescine excretion followed closely the changes in tumor volume during the course of tumor growth and regression. Urinary spermidine excretion, however, remained essentially unchanged in ovariectomized rats; spermine was barely detectable in any of the urines. There was a high positive correlation between the 24-hour urinary putrescine excretion and urine volume. In nonovariectomized rats, the mammary tumor(s) continued to grow. An unexpected result of the advanced tumor progression was that urinary excretion of both putrescine and spermidine decreased steadily with time as did urine volume. This phenomenon may be due to the fact that complex disturbances of the host metabolism, manifested in decreasing body weight.