Cytokines and growth factors in keratinocytes and sweat glands in chronic venous leg ulcers. An immunohistochemical study

The role of growth factors and cytokines in the impaired healing of chronic leg ulcers remains uncertain. The aim of this study was to determine whether changes in the amount and location of cytokines and growth factors may be associated with impaired healing in chronic leg ulcers. Biopsies from leg ulcers of 21 patients and from normal skin of nine healthy volunteers were examined immunohistochemically for selected growth factors and cytokines. Greater staining intensity was found in keratinocytes at the edges of ulcers compared to normal skin, or skin adjacent to the ulcers. Staining at the ulcer edge was more intense in nonhealing ulcers for only vascular endothelial growth factor and platelet-derived growth factor, whereas staining in the adjacent skin was more intense for all factors in the nonhealing phase. For all factors staining was cytoplasmic, suggesting production in these areas. This study shows up-regulation of the production of cytokines and growth factors in keratinocytes of chronic leg ulcers that is greater when the ulcers are nonhealing.     

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 3. 7-(3,5-Disubstituted [1,1'-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids and their lactone derivatives

The syntheses of a series of 7-(3,5-disubstituted [1,1'-bephenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids and their lactones are reported. Intrinsic 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitory activity is enhanced markedly when the biphenyl moiety is substituted by chloro or methyl groups at positions 3 and 5 and a fluoro group at position 4'. These substitutions, followed by resolution, provided compounds 100(+) and 110(+) with 2.8 times the intrinsic inhibitory activity of compactin. Compound 100(+) was shown to possess the same chirality in the lactone ring as compactin by single-crystal X-ray crystallography.     

A phase II study of 5-fluorouracil and leucovorin in advanced carcinoma of the esophagus.

Thirty-five patients with advanced epidermoid carcinoma of the esophagus were treated with 5-fluorouracil (5-FU) 425 mg/m2 and leucovorin 20 mg/m2, day 1-5 every 28 days. Six patients had a partial response (95% confidence limit, 7-35%) with a median response duration of 32 weeks. The median survival time of the patients on study was 14 weeks. The toxicity was acceptable, with only two patients experiencing severe hematologic toxicity and one patient experiencing severe nausea and vomiting. The addition of leucovorin at this dose level in this population of patients with advanced disease does not appear to enhance the activity of 5-FU for patients with squamous cell cancer of the esophagus. Since only a small percentage of patients experienced significant toxicity, a higher response rate could be achieved in patients treated with the maximally tolerated dose.     

Subtype classification of the presynaptic alpha-adrenoceptors which regulate [3H]-noradrenaline secretion in guinea-pig isolated urethra.

1. The following experiments were carried out to investigate the presence and type of functional presynaptic receptors in adrenergic nerves of the guinea-pig urethra. 2. The urethra from male guinea-pigs was incubated with [3H]-noradrenaline and superfused with Tyrode solution in vitro. The fractional secretion of [3H]-noradrenaline evoked by 300 electrical pulses was measured. 3. The [3H]-noradrenaline secretion was positively frequency-dependent, yielding a half-maximal secretion at 8 +/- 5 Hz. Stimulation was usually applied at 5 Hz. 4. The [3H]-noradrenaline secretion was not altered by noradrenaline (1 or 100 microM), norephedrine (1 microM), isoprenaline (0.1 microM), 5-hydroxytryptamine (10 microM), oxotremorine (10 microM), adenosine (0.2 mM), propranolol (1 microM), atropine (1 microM) or 8-phenyltheophylline (10 microM). 5. The [3H]-noradrenaline secretion was enhanced by clonidine (3 microM), chlorpromazine (10 microM), metitepine (1 microM), 4-aminopyridine (0.5 mM), tetraethylammonium (2 mM), 3-isobutyl-1-methylxanthine (4 mM), 8-bromo cyclic AMP (1 mM) and forskolin (25 microM). 6. The alpha-adrenoceptor antagonists rauwolscine, yohimbine, phentolamine, prazosin and AR-C 239 maximally enhanced the [3H]-noradrenaline secretion to about 300% of control. The partial alpha-adrenoceptor agonist oxymetazoline maximally enhanced the secretion to about 200% of control. The order of apparent EC50 values was rauwolscine less than yohimbine less than phentolamine less than oxymetazoline less than prazosin less than AR-C 239.(ABSTRACT TRUNCATED AT 250 WORDS)