Fiberoptic and conventional phototherapy effects on the skin of premature infants.

To evaluate the effects of conventional phototherapy and fiberoptic phototherapy on trans-epidermal water loss in preterm infants with and without skin ointment application, 20 infants were randomly assigned to receive conventional or fiberoptic phototherapy for non-hemolytic hyperbilirubinemia. After conventional phototherapy, there were no significant differences in trans-epidermal water loss between ointment-treated and untreated areas. After fiberoptic phototherapy, trans-epidermal water loss significantly increased from ointment-treated and untreated areas, but the increase was less in treated areas.

Evaluation of in vitro and in vivo antimicrobial activity of a new topical antiinfective agent.

ST 1103 (Undecyl [4-N,N,N-trimethylammonium-(R)-3- isovaleroyloxy]-butanoate methanesulfonate) is a novel compound endowed with a broad antimicrobial spectrum. ST 1103 is able to inhibit the in vitro growth of Gram-positive bacteria (mean MIC value of 2.60 micrograms/ml), Gram-negative bacteria (mean MIC value of 27.00 micrograms/ml), yeasts and yeast-like fungi (mean MIC value of 3.76 micrograms/ml), filamentous and dermatophytic fungi (mean MIC value of 18.33 micrograms/ml). Since indirect evidence indicates a poor oral absorbtion, ST 1103 was topically administered to mice with skin infections caused by mixed inocula. In these conditions, ST 1103 was able to cure mice infected with T. quinckeanum, S. aureus as well as immunodepressed mice infected with T. quinckeanum, S. aureus and C. albicans. Conversely, miconazole (reference compound) appeared inadequate, in our experimental conditions, for a definitive therapy of the skin mycosis superinfected by staphylococcus. By using an in vitro 3D-human skin model, ST 1103 was fairly well tolerated in terms of both cell viability and release of inflammatory mediators. In a dermal tolerance study in mice, ST 1103 at a concentration of 1% did not show any sign of local irritation on both intact and abraded skin after an 8-day topical treatment. In conclusion, ST 1103 appears to be a promising candidate for treatment of cutaneous infections caused by mixed microbial pathogens.

High-performance liquid chromatographic assay for N2-[5-(hypoxanthin-9-yl)pentyloxycarbonyl]-L-arginine (ST 789) in plasma by cyclization with benzoin and fluorimetric detection.

This paper describes a new highly sensitive assay for N2-[5-(hypoxanthin-9-yl)pentyloxycarbonyl]-L-arginine, an immunomodulatory agent, required for clinical pharmacokinetic investigation. A pre-column derivatization by cyclization with benzoin in aqueous medium produces the fluorescent 2-substituted amino-4,5-diphenylimidazole fluorescing at 450 nm (excitation wavelength 310 nm). L-Arginine-acetyl-L-carnitinamide chloride (ST 857, II), another arginine derivative, was used as an internal standard. A C18 DB column (5 microns, 250 mm x 4.6 mm I.D.) and a 45:55 (v/v) mixture of 0.05 M ammonium phosphate at pH 7.2 and methanol as mobile phase were used. Linearity was ascertained in the range 5-100 ng. Extraction recovery from plasma proved to be higher than 90% in the range 5-50 ng/ml. Intra-day precision, expressed as coefficient of variation, was in the range 4.7-6.0%. The limit of quantification proved to be 5 ng/ml and the limit of detection 2 ng/ml at a signal-to-noise ratio of 5. The method is specific.

[L-propionylcarnitine taurine amide induces the metabolic recovery of the isolated postischemic rat heart]. / La L-propionil-carnitina-taurinammide induce il recupero metabolico del cuore isolato di ratto postischemico.

The effect of reperfusion with L-propionyl-carnitine-taurinammide 1 mM was evaluated on the metabolic recovery of the isolated postischemic rat heart. Data referring to the tissue concentration of the high-energy phosphates, oxypurines, nucleosides, nicotinic coenzymes, lactate and pyruvate indicate that L-propionyl-carnitine-taurinammide significantly improves the metabolism of the reperfused myocardium. In particular, ATP, creatinphosphate, GTP, sum of adenine nucleotides and the energy charge resulted 1.80, 1.83, 3.47, 1.47 and 1.20 times higher respectively than the corresponding values recorded in control reperfused heart (p < 0.01 all). These data, out of supplying the necessary biochemical support to the beneficial effects of L-propionyl-carnitine-taurinammide on hemodynamics obtained in previous studies, suggest that L-propionyl-carnitine-taurinammide might represent a useful tool for the pharmacological treatment of myocardial infarction.

In vitro activation of murine peritoneal exudate cells (PEC) and peritoneal macrophages by ST 789.

ST 789 is a new synthetic compound characterized by an amino acidic group joined to the N9 position of the hypoxanthine ring, which has been shown recently to have immunomodulating properties and minimal toxicity. The drug has been reported to protect immunosuppressed mice from microbial infections and tumour growth, and to restore the mitogen-induced proliferation of splenocytes from immunosuppressed young mice. In this study, we show that in vitro addition of ST 789 is able to markedly augment the sheep red blood cells (SRBC) phagocytosis by PEC, and to potentiate the cytotoxic activity of peritoneal exudate (PE) macrophages (M phi) vs the L-M tumour cell line. We also found that ST 789 enhanced the rIFN-gamma-induced NO2- release from cultured PE M phi. Similarly, in vitro addition of ST 789 to the latter cultures significantly increased the production of interleukin 1 (IL-1) and tumour necrosis factor (TNF) induced by lipopolysaccharide (LPS). These studies demonstrate that ST 789 is a potent phagocyte activator for the induction of cytokine release, phagocytosis and cytotoxic activity against tumour cells in vitro.

ST789: a new synthetic immunomodulator.

ST 789 is a synthetic compound which belongs to a new family of hypoxanthine derivatives exhibiting an aminoacidic function at the N-9 position of the purine ring. Available literature indicates that hypoxanthine derivatives exhibit well established immunomodulant properties. Furthermore, the addition of arginine to these molecules proved able to strongly enhance their immunomodulant activity. We review here the immunomodulant properties of both arginine and arginine-containing compounds, and mostly of ST 789.

Pharmacokinetic investigation of ST 789 in rats and mice.

Pharmacokinetics of ST 789 were investigated in rats and mice after oral, intravenous, subcutaneous and intramuscular routes. A HPLC method validated for pharmacokinetic studies allowed the Authors to assay ST 789 concentration in plasma, urine and tissues. ST 789 interacted poorly with albumin and plasma proteins. Blood-to-plasma concentration ratio proved to range on average from 1.3 to 2.0 in both in vivo and in vitro studies. Plasma concentration-time behaviour after i.v. injection fitted according to the open three-compartment model; after subcutaneous and intramuscular routes two phases were observed and after oral route the absorption and one elimination phases were detected. Pharmacokinetics of ST 789 proved to vary linearly with the dose administered. Cumulative urinary excretion after parenteral administration ranged on average 60-80% and cumulative biliary excretion was 9.47% of the dose given. Oral administration allowed only 2.5% of the drug given to be excreted in urine, this leading to conclude that this drug is poorly absorbed through the intestine wall. After oral administration ST 789 produced relatively high concentration in lungs and lymphatic tissues, this leading to hypothesize a lymphatic component in its enteral absorption.

Immunorestorative properties of ST 789 on experimentally immunosuppressed and infected mice.

ST 789, a newly synthesized chemical characterized by an aminoacidic group joined to the N9 position of the hypoxanthine ring, has recently been shown to be endowed with immunomodulatory properties. In this study we tested ST 789 in vivo for protective effects in Cyclophosphamide-immunosuppressed CD1 mice experimentally infected with several bacterial and fungal pathogens. We found that immunosuppressed mice infected with either fungi or bacteria were significantly protected, as evaluated both by percent mortality and survival time, when treated with doses of ST 789 even as low as 0.2 mg/kg/day. We also observed a marked synergism when the mice were first treated with ST 789 and then additionally treated with subeffective doses of antibiotics such as Amphotericin B, Ceftazidime, and Gentamicin. Even though further studies are required to elucidate the mechanisms underlying the ST 789 effects, these results show that ST 789 is a very promising new immunomodulator whose therapeutic potential has yet to be fully exploited.

Profile of activity of a new anti-inflammatory agent, ST 679 (MED 15).

ST 679 dose-dependently inhibited carrageenan-, concanavalin A-, and nystatin-induced oedema. Studies in rats with adjuvant arthritis showed that a long dosing regimen inhibited primary and secondary lesions. ST 679 was significantly active in reducing the severity of the already established disease and, when given in a short course at the time of adjuvant injection, permanently prevented the development of secondary lesions. Experimental allergic encephalomyelitis in guinea-pigs was not affected by ST 679.

High-performance liquid chromatographic evaluation of PCF 39, a new immunomodulator agent.

An high-performance liquid chromatographic analysis of PCF 39, N2-[5-(hypoxanthin-9-yl)pentyloxycarbonyl]-L-arginine, with ultraviolet detection, has been devised and validated. The main pharmacokinetic results encountered for rats treated intravenously with PCF 39 at a dose of 100 mg/kg are described.

Slow release nifedipine in the treatment of Raynaud's phenomenon.

An ever increasing interest is shown towards calcium-antagonist drugs and in particular to nifedipine in the treatment of Raynaud's Phenomenon (R.P.) On this matter a randomized double-blind study with 40 mg/die slow release nifedipine versus placebo was carried out for 30 days on 24 patients affected by R.P.-idiopathic in 16 cases and secondary in the remaining 8 cases. The evaluation of the clinical situation (hand ischemic attacks, pain, skin trophism) and the structural one (capillaroscopy of the finger nail bed and strain-gauge digital plethysmography) could be performed on 17 patients since 7 dropped out. From the clinical point of view an improvement was observed especially in the reduction of the ischemic attacks (88.8% of patients treated with nifedipine vs. 25.0% treated with placebo). Capillaroscopic results showed an improvement in 100% of the cases treated with nifedipine vs. 12.5% with placebo (p less than 0.001), as well as an improvement of the basal digit blood pressure values and after cold test in 88.8% of patients treated with nifedipine vs. 12.5% treated with placebo (p less than 0.005) and (p less than 0.0025) respectively.

Antirheumatic drugs and macrophage function: effects on tumour cell growth in vitro.

The ability of the antirheumatic drugs D-penicillamine, chloroquine and levamisole to modify macrophage-mediated inhibition of tumour cell growth in vitro was investigated. Increasing numbers of rat peritoneal macrophages were cocultured with a fixed number of ascites hepatoma AH-13 rat tumour cells. Tumour cell growth was assessed as the uptake of 3H-thymidine (3H-TdR) by AH-13 cells at the end of a 24 h period of coculture with macrophages treated in vitro or in vivo with the various drugs. In vitro, preincubation of macrophages with D-penicillamine or chloroquine (50 - 250 micrograms/ml) increased tumour cell 3H-TdR incorporation, compared to cultures with untreated macrophages. Macrophages from rats treated with D-penicillamine or chloroquine (50 mg/kg/day orally) for 4 days similarly increased tumour cell 3H-TdR incorporation, compared to cultures with macrophages from untreated rats. These effects persisted for at least 3 to 4 weeks of treatment. Preincubation with levamisole (10 - 100 micrograms/ml) in vitro had no effect on macrophage-mediated inhibition of tumour cells, whereas increased tumour cell 3H-TdR incorporation was observed in cultures with macrophages from rats treated with levamisole (5 mg/kg/day orally) in vivo. Macrophages from rats with experimentally induced chronic inflammation, i.e. adjuvant arthritis, were found to increase tumour cell 3H-TdR incorporation, compared to macrophages from nonarthritic rats. This trend was further enhanced by treatment with D-penicillamine, chloroquine or levamisole.

The effect of some antirheumatic drugs in vivo on the response of spleen cells to concanavalin A in rats with chronic inflammation.

During the course of adjuvant arthritis in rats adherent spleen cells inhibited the response of spleen lymphocytes to the T-cell mitogen concanavalin A (Con A). The effects of 14 days treatment with various antirheumatic drugs on spleen cell responsiveness to Con A were investigated. Two nonsteroidal anti-inflammatory drugs, indomethacin (1 mg/kg/day p.o.) and acetylsalicylic acid (200 mg/kg/day p.o.) did not modify the spleen cell response, whereas treatment with chloroquine (50 mg/kg/day p.o.) or levamisole (5 mg/kg/day p.o.) further increased the inhibitory effects of the adherent suppressive spleen cells. On the contrary, treatment with sodium aurothiomalate (10 mg/kg/day i.m.), D-penicillamine (50 mg/kg/day p.o.) or pyritinol (50 mg/kg/day p.o.) significantly enhanced the response of the lymphocytes to Con A. In addition to the effects on spleen cell responsiveness, the ability of the various drug treatments to modify the polyarthritic lesions of the disease was investigated. It is suggested that this model may provide a valuable approach for evaluating the effects of antirheumatic drugs in vivo on immunological responsiveness during chronic inflammatory disease.

Chronic inflammation in adjuvant arthritic rats correlates with enhancement of 12-L-HETE-synthesis.

The development of chronic inflammation in adjuvant arthritic rats was found to be strongly correlated with the appearance in serum of a factor (HSF) which enhanced the formation of 12-L-HETE by platelet-lipoxygenase, and with the serum-concentration of 12-L-HETE. The latter was determined by scanning at 235 nm after extraction and high performance thin-layer chromatography. Arthritic rat platelet-rich plasma (PRP) converted exogenous arachidonic acid to 12-L-HETE at a rate 2.6-fold higher than control rat PRP. By resuspending arthritic rat platelets in normal rat plasma, and normal rat platelets in arthritic rat plasma, this increase in conversion rate was found to be caused by HSF present in the arthritic rat plasma. Treatment of arthritis with non-steroidal anti-inflammatory drugs inhibited HSF activity as well as the increase in serum-12-L-HETE concentration, which indicates a prostaglandin-mediated mechanism of HSF synthesis or release.

D-penicillamine, lymphocytes, and macrophages: an account of experimental investigations in vivo.

A short oral treatment with D-penicillamine of normal rats increased responsiveness of spleen and lymph node lymphocytes to concanavalin A, depending on the presence of functionally intact macrophages. This effect vanished after 2 to 3 wk despite continued treatment. In adjuvant arthritic rats, a suppressed response of lymph node lymphocytes occurs concomitantly with the development of the secondary lesion. This inhibition caused by suppressive macrophage activity was abolished by D-penicillamine treatment, which enhanced T helper cell function. This effect disappeared when permanent crippling developed with residual minimal inflammatory reaction. These findings may give further insight into the drug's effects and side effects.

Adjuvant arthritic rat serum enhances HETE1 biosynthesis.

The effect of serum from adjuvant arthritic rats in the chronic inflammatory stage, on lipoxygenase activity in either rat peritoneal macrophages, intact rabbit platelets or the cytoplasmic fraction of horse platelet homogenates was studied. All preparations produced significantly more HETE from exogenous arachidonic acid in the presence of arthritic serum than normal serum. This effect was known not to be associated with the lower albumin level in arthritic serum, and it was specific for the lipoxygenase pathway of arachidonic acid metabolism as there was no effect on cyclo-oxygenase activity. The presence of an arthritic serum factor(s), with a molecular weight in the range of 100,000 as indicated by gel-filtration experiments, which specifically enhances the synthesis of HETE, is proposed.

Inhibition of adjuvant arthritis by intraperitoneal administration of low doses of silica.

Daily intraperitoneal administration from day 3 to day 10 post-adjuvant of crystalline silica in doses 1.5-3.1 mg/kg per day or of amorphous silica in doses of 12.5 mg/kg per day inhibited the development of adjuvant arthritis mostly suppressing the swelling of the non-injected paw. These doses of silica did not impair the carbon clearance. Higher doses of silica (25 mg/kg per day of the crystalline form and 50 mg/kg of the amorphous form) administered from day 17 to day 24 post-adjuvant had no effect on the already established disease.

Macrophages from adjuvent arthritic rats preferentially synthetize prostacyclin.

Peritoneal macrophages obtained from rats 21 days after induction of adjuvant arthritis and maintained in culture for 20 h in presence of [14C]-arachidonic acid and 10% foetal calf serum were found to have increased capacity for synthetizing prostacyclin and diminished capacity for synthetizing PGE2 compared with macrophages from normal rats. Similar results were obtained when foetal calf serum was replaced by either normal or arthritic rat serum. Orally administered indomethacin inhibited the increased synthesis of prostacyclin.