Inhibitory action of tranilast, an anti-allergic drug, on the release of cytokines and PGE2 from human monocytes-macrophages.

Tranilast, an anti-allergic drug that inhibits the release of substances such as histamine and prostaglandins from mast cells, has been reported to improve keloids and hypertrophic scars which originate from the abnormal proliferation and excessive collagen accumulation of fibroblasts. It has been considered that various chemical mediators produced by inflammatory cells play important roles in the development of keloids and hypertrophic scars. We therefore studied the effect of tranilast on the release of chemical mediators including transforming growth factor (TGF)-beta 1, interleukin (IL)-1 beta and prostaglandin (PG) E2 which are produced by the human monocytes-macrophages, and estimated whether these mediators induce collagen synthesis and cell proliferation of normal skin fibroblasts. Tranilast inhibited the release of TGF-beta 1, IL-1 beta and PGE2 from the human monocytes-macrophages. TGF-beta 1 (25-200 pM) enhanced the collagen synthesis by fibroblasts. IL-1 (0.1-1 U/ml) increased the proliferation and conversely decreased the collagen synthesis. PGE2 (2 micrograms/ml) enhanced the collagen synthesis. These results suggest that tranilast suppresses collagen synthesis by fibroblasts through inhibiting TGF-beta 1 and PGE2 production and cell proliferation by fibroblasts through inhibiting IL-1 production by inflammatory cells such as macrophages.     

Environmental monitoring and assessment of short-term exposures to hazardous chemicals of a sterilization process in hospital working environments

In order to assess short-term exposures to ethylene oxide, formaldehyde and glutaraldehyde in a sterilization process, the authors conducted continuous environmental monitoring of these chemicals in the breathing zone of workers in 2 hospitals. The arithmetic mean of ethylene oxide was 1.2 ppm near unventilated cabinets housing sterilizing materials, and environmental concentrations of ethylene oxide could not be reduced under threshold limit values time weighted average by only managing general ventilation. Environmental concentration of formaldehyde was lower in a properly ventilated pathology division in which no large specimens were stored (0.3 ppm) than in the pathology division where large specimens were stored (2.3 ppm). Although environmental concentrations of glutaraldehyde in an endoscopy unit with proper general ventilation were not detectable, environmental concentration levels in an endoscopy unit without general ventilation system were 0.2 and 0.5 ppm. According to the results of environmental monitoring in the breathing zone of workers, extremely high concentrations were observed in some work practices (ethylene oxide, 300 ppm; formaldehyde, 8.6 ppm; glutaraldehyde, 2.6 ppm). In order to avoid occupational exposures to these chemicals and prevent potential chronic and acute health hazards, good communications with these chemicals, good work practices, appropriate personal protective equipment, and engineering controls should be required.     

The inhibition mechanism of histamine release by N-(3,4-dimethoxycinnamoyl) anthranilic acid

N-(3,4-Dimethoxycinnamoyl) anthranilic acid (N-5') is an inhibitor of IgE-mediated histamine release from mast cells. To elucidate inhibition mechanism, effects of N-5' were examined under various conditions using peritoneal exudate cells and isolated mast cells of rats. N-5' inhibited histamine release induced by antigen, ionophore A23187, ATP, dextran and phospholipase A2. But the release induced by compound 48/80 or ionophore X537A was not inhibited. Influx of Ca++ into mast cells and ATP consumption were inhibited. Based on these results, it is presumed that N-5' interferes with the energy-requiring system and/or Ca++ influx resulting in the inhibition of histamine release.     

The effect of prednisolone on substance P-induced vascular permeability in mice

The effect of prednisolone on the substance P (SP)-induced vascular permeability increase in male ddY, WBB6 F₁–+/+ (control) and WBB6 F₁-W/W^v (no mast cell in skin or internal organs) mice was investigated. 1) SP (1–10 000 pg/site) increased vascular permeability in ddY, WBB6 F₁–+/+ and WBB6 F₁-W/W^v mice ears. 2) SP (100 pg/site)-induced vascular permeability was inhibited by prednisolone (10 mg/kg) administered intraperitoneally 3 to 12 hours prior to the elicitation of the reaction in ddY mice. When dexamethasone at a dose of 1 mg/kg was administered intraperitoneally 2 to 24 hours prior to the elicitation of the reaction, significant inhibition was observed. When prednisolone was administered intraperitoneally 8 hours prior to the elicitation of the reaction, the SP-induced capillary permeability increase in both ddY and WBB6 F₁-W/W^v mice was clearly inhibited by the drug at doses of 5 and 10 mg/kg. 3) Diphenhydramine (1 and 10 mg/kg) inhibited SP-induced vascular reaction in ddY mice but not in WBB6 F₁-W/W^v mice. 4) Atropine (10 mg/kg) inhibited SP-induced vascular reaction in both ddY and WBB6 F₁-W/W^v mice. But acetylcholine did not cause an increase of vascular permeability in ddY and WBB6 F₁-W/W^v mice ears. 5) Prednisolone (5 mg/kg) inhibited histamine- and serotonin-induced vascular permeability in ddY and WBB6 F₁-W/W^v mice ears. 6) Prednisolone (5 and 10 mg/kg) inhibited the SP-induced histamine release from ddY mice peritoneal mast cells. These results suggest that the vascular effect of SP is mediated by both mast cell dependent (release of histamine from mast cells) and mast cell independent mechanisms. Prednisolone inhibits the SP-induced vascular permeability mediated by both mechanisms in mice.     

Sensitization to mechanical stimulation by inflammatory mediators and by mild burn in canine visceral nociceptors in vitro

Hyperalgesia to mechanical stimulation and heat is commonly observed in inflamed conditions. Although sensitization to heat is well documented and its mechanism has also been well studied, it remains unclear whether and how nociceptors are sensitized to mechanical stimulation. Therefore we conducted in vitro investigation of which inflammatory mediators (bradykinin, histamine, prostaglandin E2, and protons) sensitize nociceptors to suprathreshold mechanical stimulation and at what concentrations. In addition, we studied the effects of possible second messengers for these mediators downstream of the receptors and also the effects of mild burn. Single polymodal receptor activities were recorded in canine testis-spermatic nerve preparations excised from deeply anesthetized dogs. Mechanical stimulation was applied to the identified receptive field for 10 s with a servo-controlled mechanical stimulator. Bradykinin at 0.001 microM induced neither excitation nor facilitation of the mechanical response; however, it facilitated the mechanical response at 0.01 microM and higher, levels at which significant excitation was also induced by bradykinin alone. Histamine excited the nociceptor and sensitized it to mechanical stimulation at 10 microM and higher. PG E(2) also sensitized the mechanical response, but starting at 1 microM, without inducing excitation by itself. The effects of two possible intracellular messengers for these mediators were studied using forskolin (10 microM), which increases intracellular cAMP, and a protein-kinase-C-stimulating phorbol ester, phorbol 12,13-dibutyrate (0.1 microM). Both substances reversibly facilitated the mechanical response of testicular polymodal receptors. In contrast, low-pH solution (pH: 6.6-4.5) seldom induced excitation and failed to facilitate the mechanical response. After 55 degrees C, 30-s heat stimulation, testicular polymodal receptors were sensitized to mechanical stimulation. These results demonstrated that inflammatory mediators and burn sensitized nociceptor responses to mechanical stimulation and provide support for the idea that peripheral nociceptor sensitization is a mechanism involved in hyperalgesia to mechanical stimulation in inflamed tissues.     

Myocardial "elektive disseminierte Parenchymnekrose" revisited

A 43-year-old man was found to show cardiac arrest during overnight detention in a police station. The autopsy revealed no abnormality other than a fatty liver on gross examination. Microscopic examination of the heart showed typical disseminated hypoxemic foci of necrosis with hemorrhaging but without infiltration of inflammatory cells, which Büchner, about 60 years ago, proposed as a sign of acute coronary insufficiency without acute coronary occlusion due to massive hemorrhage. However, the disseminated focal hemorrhagic necrosis of microscopic size found in the present study appears to be one of early signs of ischemia in the heart muscle and to occur frequently at silent ischemic heart attacks during daily life.     

Pharmacokinetics of trimetrexate and dapsone in AIDS patients with Pneumocystis carinii pneumonia

The objective of this study was to determine the pharmacokinetics of trimetrexate and dapsone in AIDS patients with moderate to severe pneumocystis pneumonia. Trimetrexate, leucovorin, and dapsone were administered for 21 +/- 3 days in the following doses: trimetrexate glucuronate, 45 mg/m2; leucovorin, 20 mg/m2; and dapsone, 100 mg daily. The pharmacokinetics of trimetrexate, dapsone, and dapsone's metabolite, monoacetyldapsone, were determined at three separate periods over the course of treatment. Serial blood samples were obtained over 24 hours after dosing and analyzed for trimetrexate, dapsone, and monoacetyldapsone, and pharmacokinetic parameters were determined. The mean parameters obtained for the early, mid-, and late collection periods were the following: trimetrexate: t1/2 = 8.29, 9.15, 10.00 hr; AUC = 16.85, 22.38, 24.49 mg.hr/l; CI = 5.58, 4.14, 3.96 l/hr, respectively. DDS: t1/2 = 14.99, 16.59, 15.13 hr; AUC = 30.60, 35.29, 36.08 mg.hr/l; CI = 3.82, 3.49, 3.01 l/hr, respectively. Monoacetyldapsone: t1/2 = 20.25, 18.66, 16.32 hr; AUC = 24.05, 24.06, 23.86 mg.hr/l, respectively. No statistically significant changes in pharmacokinetics for trimetrexate or dapsone were observed over the 21 +/- 3 day course of treatment. The results suggest that there are no major interactions between trimetrexate and dapsone when administered together in acutely ill patients.